Zeaxanthin formulations with additional ocular-active nutrients, for protecting eye health and treating eye disorders

ABSTRACT

Oral formulations for promoting eye health, and in particular for preventing or treating macular degeneration, are disclosed, containing zeaxanthin, a carotenoid pigment, and at least two or more additional ocular-active nutrients selected from lipoic acid, omega-3 fatty acids, plant-derived compounds such as flavonoids, anthocyanins, or polyphenolics, taurine, carnitine, Coenzyme-Q10, carnosine, and nutrients that stimulate the production of glutathione. Processes are disclosed for identifying ocular-active nutrients that will interact in a synergistic and potentiating manner with zeaxanthin, to provide better and more effective protection, for eye health, than can be provided by zeaxanthin alone. Additional optional agents include zinc, vitamin E, and vitamin C.

RELATED APPLICATION

This application claims the benefit under 35 USC 119(e) of provisionalapplication No. 60/453,522, filed on Dec. 23, 2002.

FIELD OF THE INVENTION

This invention is in the fields of biochemistry, pharmacology, andnutritional supplements, and relates to orally-ingested formulations fortreating or preventing eye diseases and vision problems.

BACKGROUND OF THE INVENTION

Hundreds of different dietary supplements, under thousands of differentbrand and product names, are being marketed to the public in the U.S.and elsewhere, by means of advertising promises and claims which suggestthat these products can help prevent or treat eye diseases, and maintaineye health. Faced with an overwhelming glut of competing promises andproducts, nearly all of which are unproven and many of which have onlytenuous and flimsy support, it has become effectively impossible forpeople who are concerned about eye health to know which products willhelp, and which are merely preying on innocent victims whose vision isdeteriorating, either because of general aging problems, or due tospecific diseases, infections or injuries.

Indeed, severe uncertainties and doubts about which dietary supplementsare effective extend to full-time professionals who specialize in eyeresearch, or in treating eye diseases. Many examples to support thisassertion can be cited, including numerous current and recent articles,in respected scientific and medical journals, stating that not enoughevidence is available to allow physicians to know whether to recommendvarious candidate dietary supplements to their patients.

Along those same lines, the recent AREDS (Age-Related Eye Disease Study)study, which was organized and carried out by the National Eye Instituteat a cost of tens of millions of dollars, tested vitamins C and E (aswell as beta-carotene) at high dosages. They offered a low and weaklevel of protection against macular degeneration, in some but not all ofthe patient categories, in the AREDS-1 trial. Similarly, zinc at veryhigh dosages (80 mg/day), by itself, offered a low and weak level ofprotection in some categories of patients. When vitamins A/C/E and zincwere combined, the level of protection increased, especially amonglate-stage macular degeneration sufferers. Accordingly, the results andfindings of the AREDS-1 trial are not regarded as strong or compelling,when compared with the potential benefits of zeaxanthin, and in recentyears it also has become clear that high dosages of vitamin A or itsprecursor, beta carotene, offer little or no serious hope for providingany significant protection against macular degeneration, or any otherserious eye disorders among people who receive minimal baseline levelsof vitamin A.

As a direct response to the positive claims of the AREDS managers, oneskilled observer (Siegel 2002) publicly and openly complained that thepurported benefits could be teased out of the data only by massaging thedata in ways that, instead of being objective, impartial, andscientific, were instead biased and intended to locate somethingpositive to report, to offset the fact that the entire remainder of thestudy had spent many millions of dollars but had come up empty. In thewords of that expert, “In my opinion the AREDS investigators promoted anonsignificant result into a conclusive recommendation. Here is how theydid it . . . the message that should have emerged from AREDS is thatthese treatments failed to demonstrate efficacy in preventing AMD andare not recommended for that use.” Even reviewers who endorsed the AREDSfindings had to include various cautions and caveats; as one example, inan editorial that accompanied the AREDS report, in the same issue of thesame journal, the reviewer had to include statements such as, “Theexclusion of the subgroup of patients in Category 2 from many of theanalyses because of the low incidence of primary outcome events introubling because it came after review of the data.”

Other experts in eye research, and ophthalmologists who specialize intreating patients with serious eye problems, do not and cannot agree onthe roles of either or both of two carotenoid pigments that are known toexist naturally in the retina. Those two pigments are called lutein andzeaxanthin. However, even though nearly 20 years have passed since Boneet al 1985 identified those two carotenoid pigments as the agents thatgive the “macula” (a small yellowish spot in the center of the retina,which is crucial for clear vision) its yellowish color, experts in eyeresearch and eye diseases cannot and do not agree on what roles thosetwo carotenoids play in the retina, or whether either or both of themshould be recommended as dietary supplements. Evidence to support andprove this conclusion is available from numerous sources, both publishedand unpublished. As one example of a published report, a large panel ofhighly respected experts who specialize in retinal diseases was broughttogether in 1998 by the National Eye Institute (NEI), and the expertswere asked to develop strategic proposals and recommendations that wouldguide the NEI's funding for eye research over the next five years. Thatpanel reviewed a wide range of options and candidate treatments, andspecifically identified and named about 60 candidate treatments that theexpertts thought were deserving of careful scientific study and researchgrants. Even though that panel of experts identified nearly 60 specificresearch leads, it never even mentioned lutein or zeaxanthin. Thatomission could not have been a mere oversight due to a lack of availableinformation, since a number of members of that panel had previouslywritten and published papers that had explicitly discussed lutein andzeaxanthin.

Numerous other researchers who specialize in eye and vision studies alsohave stated that no reliable conclusions can yet be reached on whetherlutein and/or zeaxanthin can actually benefit the eyes to a point wherethey should be recommended as nutritional supplements. Examples of suchrecently-published conclusions include Schalch 2000, and Jampol 2001.Schalch 2000 states, at page 38, “Epidemiological studies thereforecannot provide definite proof of the efficacy of lutein and zeaxanthinin AMD. Such studies can provide evidence of possible relatinships butcannot determine whether an effect is causal. The situation is differentwith intervention studies in which agents are administered on adouble-masked, placebo-controlled, randomized basis and results areevaluated using predefined efficacy parameters. In the case ofsupplementation with lutein and zeaxanthin, where only small to moderateresponses can be expected, only studies such as these are likely toprovide a definite answer as to an effect of lutein and zeaxanthin onAMD. However, the specific time-course and nature of this disease makesthe design of such trials difficult.” Jampol 2001, at page 1534, states,“In view of previous studies suggesting that beta-carotene might beharmful in smokers and may be associated with a greater risk of lungcancer, beta carotene should probably not be used by smokers and recentex-smokers. An argument could be made that another carotenoid, lutein orzeaxanthin, could be substituted for beta carotene, but the values andrisks of other carotenoids [apparently referring again to lutein andzeaxanthin] is unknown at this time.”

As another example of the uncertainties and doubts that surroundzeaxanthin among skilled physicians who treat eye diseases, the Inventorhas personal knowledge of a patient who has the “wet” (or “exudative”)form of macular degeneration. This disease is characterized byaggressive growth of capillaries in and around certain layers of theretina, and it leads to rapid and devastating loss of vision. The bestknown treatment for wet AMD is called laser photocoagulation, orphotodynamic therapy. It uses a drug called verteporfin, which isactivated by a laser that is shone directly into the eyes of patientswho have taken the drug. In October of 2003, a ZeaVision customer (amale in his late 70's) who was taking zeaxanthin capsules on a dailybasis was scheduled to have a laser treatment using verteporfin, at theWilmer Eye Institute in Baltimore, which is affiliated with the JohnsHopkins School of Medicine. This patient told his treating physician,who is one of the top experts in the world on treating maculardegeneration, that he was taking zeaxanthin capsules on a daily basis.The treating physician suggested that the patient should stop takingzeaxanthin, since it probably would not help. Despite that suggestion,the patient continued taking zeaxanthin, up through the date of thetreatment and continuing thereafter. The results of that treatment, asmeasured up until the date this is being written, have been outstanding,and have been much better than was expected by the treating physician.That discovery is the subject of a recently-filed provisional patentapplication that will be disclosed to the companies that manufacture andsell verteporfin, and to a number of physicians who performlaser-verteporfin treatments, so they can evaluate it in a clinicaltrial using numerous patients. For now, the point worth noting is this:when advised that a patient suffering from wet macular degeneration wastaking zeaxanthin, one of the top eye experts in the world advised thepatient that he should stop taking it.

This current invention centers on zeaxanthin, which is believed by theInventor to be an essential and crucial ingredient in any optimal ornear-optimal pharmaceutical formulations and/or dietary supplements thatwill be truly effective in protecting, treating, and otherwise improvingvarious aspects of eye health. A number of reasons for believing andasserting that zeaxanthin is and will be the essential and crucialingredient in such formulations (including factors indicating thatzeaxanthin will perform substantially better than lutein, in this role)are set forth below, to justify these assertions and beliefs by theInventor despite lingering refusals by other skilled researchers and eyecare companies to recognize zeaxanthin's role as a crucial and essentialagent for protecting and preserving eye health.

It might be asserted that each factor summarized in the next section isalready known and published, in the prior art. However, it must also berecognized that (i) these factors have never previously been combinedand correlated, in the manner set forth herein; and, (ii) thenon-obviousness of the invention disclosed herein must also be evaluatedin light of evidence which clearly shows that numerous highly-skilledexperts do not believe zeaxanthin has any proven role in protecting orrestoring eye health.

Information on Zeaxanthin in Eye Health

The use of zeaxanthin for treating and preventing macular degenerationis described in several US patents, including U.S. Pat. No. 5,747,544(Garnett et al 1997) on methods of use, and reissue patent Re-38,009(Garnett et al 2003, which replaced U.S. Pat. No. 5,827,652, Garnett etal 1998) on formulations for human ingestion. The contents and teachingsof those patents are incorporated herein by reference, as though fullyset forth herein.

Additional review articles that discuss the roles and the assumed,purported, or likely effects of zeaxanthin and lutein, in mammalianeyes, is provided in a number of articles, including Snodderly 1995,Landrum et al 1997, Schalch et al 1999, Schalch 2000, and Semba et al2003.

Zeaxanthin and lutein both belong to a class of molecules calledcarotenoids, which are created by plants. “Carotenoids” were given thatname, because they were first isolated from carrots.

Carotenoids have two traits that make them very important in nature andnutrition: (1) they're very good at absorbing ultraviolet (UV) and bluelight; and (2) just like vitamins, they cannot be synthesized inside thecells or bodies of humans, or other mammals. Therefore, humans and othermammals must eat carotenoids in food, or in dietary supplements, to getthe amounts they need.

Since the UV radiation in direct sunlight, shining directly on cells fornumerous hours each day, is strong enough to kill any type ofunprotected cell, carotenoids play crucially important role in plants,and in many types of bacteria. Hundreds of slightly different types ofcarotenoids have evolved in different species of plants and bacteria;over 600 distinct types of carotenoids have been identified in nature,and every year another dozen or more are announced. All of thosecarotenoids are synthesized only in plants or bacteria. Animals(including humans) simply cannot make carotenoids; instead, we must eatthe carotenoids we need, in our diets.

An important fact of physics is that light rays with very shortwavelengths, in the ultraviolet (“UV”), near-ultraviolet, and deep blueparts of the spectrum, contain the most energy of any wavelengths in ornear the visible spectrum. UV and near-UV rays are what turn sunburnedskin a painful shade of red. Sunburn is a defense mechanism; when theouter layers of skin become damaged, they respond by swelling up,becoming engorged with blood, histamine, and other agents, andgenerating and recruiting higher levels of pigment in an effort toreduce the amount of additional damage. UV rays will kill the outermostlayers of cells of the skin; when sunburned skin begins to peel, thoseare dead skin cells, coming off.

In the same way, UV rays are a very effective way to sterilize surfaces,because they will kill nearly any types of viruses or bacteria they canreach and hit.

UV rays inflict this type of damage by breaking apart biomolecules moreor less randomly. When a ray or photon of UV radiation hits varioustypes of chemical bonds that hold together adjacent atoms inbiomolecules, it typically breaks the bond between those two atoms,thereby splitting the molecule into two fragments.

By splitting apart biomolecules on a random basis, UV radiation inflictstwo different types of toxic and potentially lethal damage on cells.First, UV radiation will directly break apart the long molecular strandsthat make up protein and DNA. Since protein and DNA are crucial to anycell, this type of damage will directly kill cells, if it continues longenough. The second mechanism is this; when UV radiation hits a moleculethat contains oxygen, it often causes an oxygen-containing fragment tobe broken off of the molecule, in a way that creates a highly unstableand reactive “oxygen free radical”. Because of complicated factorsinvolving the electrons in an oxygen atom's “valence shell”, theseunstable free radicals will attack, alter, and damage nearly any type ofbiomolecule.

To minimize that type of damage from oxygen free radicals, cells usevarious types of anti-oxidants, which are molecules that will attractand react with oxygen free radicals. A good anti-oxidant molecule willbind any oxygen free radicals into larger molecules, which are stableand will not attack other molecules. This type of neutralizing reaction,by anti-oxidant molecules which absorb and neutralize oxygen freeradicals, is often referred to as “quenching,” in a manner similar toquenching a fire.

Carotenoids are very effective anti-oxidants, and they can quench andneutralize oxygen free radicals. Therefore, plants evolved withcarotenoids as a special class of protective molecules, which canminimize damage that otherwise would be cause by ultraviolet radiation.The surface cells that cover plant leaves contain large quantities ofcarotenoids. Indeed, carotenoids are what causes tree leaves to turnred, orange, and gold in the fall. Since carotenoids absorb light withblue and violet wavelengths, the wavelengths that bounce off and arereflected and emitted, by the leaves, are at the other end of the colorspectrum, in the red, orange, and yellow region. When cold weatherarrives and tree leaves become inactive, any green chlorophyll whichremains in the leaves is degraded more rapidly than carotenoids, whichare rather stable molecules. This causes the red, yellow and orangecarotenoids to become the dominant colors in leaves, during the fall.

Bacteria growing in places exposed to direct sunlight for hours requirethe same type of protection against toxic UV rays. This is why scum thatgrows on rocks in a river (if it is not made of green algae withchlorophyll) is usually some shade of yellow, brown, or orange. Bacteriathat can survive in such locations have evolved the ability tosynthesize carotenoids, to protect the bacteria from being killed by UVradiation.

Carotenoids can absorb UV radiation and neutralize oxygen free radicals,without being broken apart, because they contain numerous “conjugatedbonds”. This is a complicated term, but it can be explained by pointingout an important fact in FIG. 1, which is a drawing of the chemicalstructures of zeaxanthin and lutein (with beta-carotene also shown, forcomparative purposes).

In the straight chain portion (i.e., the chain that stretches betweenthe two “end rings”) of all three carotenoids shown in FIG. 1, thedouble bonds alternate with single bonds. This pattern of alternatingsingle-bonds and double-bonds is referred to by chemists as“conjugation”. It is important, because when a series of single anddouble bonds, all in a row or circle, are conjugated, the electrons thatform the bonds between adjacent atoms do not remain attached to specificatoms. Instead, the electrons become mobile, and they form an “electroncloud” that covers and surrounds the molecule. This same type ofsemi-mobile electron cloud also surrounds and stabilizes benzene ringsand other “aromatic” organic molecules.

This type of semi-mobile electron cloud is important, because it leadsto a remarkable result. When a carotenoid molecule is hit by a UV ray oran oxygen free radical, the molecule doesn't break. Instead, theelectron cloud is able to flex and yield, in a way that cushions andabsorbs the blow. This is comparable to someone hitting a wooden board,or a rubber tire, with a sledgehammer. The board will break, because itcannot bend or deflect. The rubber tire will not break, because it canflex and yield in a way that allows it to absorb the force of the blow.

Because their semi-mobile electron clouds are flexible and yieldingrather than rigid, carotenoid molecules can absorb numerous “hits” fromUV rays and oxygen free radicals, without being broken apart. When a UVphoton or an oxygen free radical hits a carotenoid, the destructivepower of that photon or free radical is used up and absorbed by theelectron cloud. The photon or free radical is “quenched”, so it cannotattack and damage any other molecules, such as protein or DNA. In thismanner, by absorbing and neutralizing UV radiation and oxygen freeradicals, carotenoids protect DNA, proteins, and other cruciallyimportant molecules in cells.

These facts about conjugation apply to zeaxanthin and lutein, and theylead to a crucially important difference between zeaxanthin versuslutein, the only two carotenoids that are found in the macula, acrucially-important part of the retina that sits at the very center ofthe retina. As can be seen by examining their structures, in FIG. 1, thedouble-bond in the right end ring of zeaxanthin is perfectly conjugated,since it continues and extends the same alternating double-singlesequence that appears in the straight-chain portion. Therefore, thesemi-mobile “electron cloud” created by the conjugated bonds extendsover part of zeaxanthin's right end ring.

By contrast, in lutein, the double-bond in the right end ring ismisplaced, and there is no conjugation at all, in the right end ring oflutein. Therefore, one of lutein's end rings has no electron cloud.

It should also be noted, from the chemical structures in FIG. 1, thatthe other end rings (shown on the left side of FIG. 1) of bothzeaxanthin and lutein are identical. In both molecules, the left endrings are conjugated, and have partial electron clouds covering them.This points out another important reason why zeaxanthin appears to bebetter and more effective than lutein, in protecting human retina cells.Zeaxanthin is perfectly symmetrical, end-to-end. If rotated so that itstwo end rings swap places, there is absolutely no change. By contrast,lutein is not symmetric, since its two end rings have differentstructures. If lutein is rotated, it leads to a different alignment, orstructure.

That difference between zeaxanthin and lutein (i.e., the misplaceddouble-bond in one of lutein's end rings) may seem minor, from lookingat the chemical drawings in FIG. 1. However, chemical tests have clearlyshown that zeaxanthin is more potent and effective than lutein, inabsorbing and “quenching” oxygen free radicals. This presumably is oneof the reasons why the macula, in human retinas, evolved in a way thatclearly favors zeaxanthin over lutein, as described below.

Two other points involving the structures of zeaxanthin and lutein alsodeserve mention. First, both zeaxanthin and lutein have “hydroxy” (HO—)groups attached to both of their end rings. By contrast, beta-carotene,also shown in FIG. 1, is made entirely of carbon and hydrogen atoms,with no oxygen atoms anywhere.

The fact that beta-carotene is made entirely of hydrocarbon leads to acrucial fact: it is non-polar, which means it is soluble in oilyliquids, most of which also are made only of hydrocarbons. By contrast,the presence of hydroxy groups, at both ends of zeaxanthin and lutein,leads to a crucially important difference in the way zeaxanthin andlutein behave, compared to how beta-carotene behaves, when any of thosethree carotenoids, formed in plants, are eaten by animals.

The outer membrane of any animal cell is made of molecules that areoil-soluble at one end, and water-soluble at the other end. Thesemolecules are called phospho-lipids, since they have a water-soluble“head” (which contains phosphorous) bonded to an oil-soluble “tail”(made entirely of hydrocarbons). Because of these structures,phospho-lipid molecules will spontaneously line up together, when theyare placed in a watery fluid, in a way that gives them a “bilayer”arrangement, shown in FIG. 2A. A layer that contains the water-soluble“heads” of the phospho-lipids line up so that they cover the outside ofthe cell membrane. This allows the water-soluble “heads” of thephospho-lipids to coat the outermost surface of the cell membrane with alayer that is completely comfortable in the watery liquids that surroundthe cell (including blood, lymph, and tissue gel). The center layer ofthe bilayer membrane is made of the oily hydrocarbon tails, which areattracted to each other. The inner surface of the membrane is anotherlayer of water-soluble heads, which will comfortably contact the wateryfluid (called cytoplasm) that fills the cell.

Because beta-carotene has an entirely oily structure, made of nothingbut oily hydrocarbons with no oxygen atoms or hydroxy groups, it willalign itself in a way that causes it to remain fully inside a cellmembrane, once it reaches that position. This configuration is shown inFIG. 2B.

By contrast, because zeaxanthin and lutein have water-soluble hydroxygroups at their ends, they will align themselves perpendicular to a cellmembrane, in a direction that causes them to “straddle” or “span” thecell membrane. This “membrane-spanning” alignment is illustrated in FIG.2C.

This crucial difference, in how these carotenoids will align themselvesin animal cell membranes, is a major difference between beta-carotene,versus oxygen-containing carotenoids such as zeaxanthin and lutein.Because of how carotenoids and animal cell membranes evolved, in waysthat allowed them to survive on earth despite constant bombardment bypotentially lethal dosages of ultraviolet radiation from the sun, it isno mere coincidence that most of the oxygen-containing carotenoids(including zeaxanthin, lutein, and various other carotenoids such ascanthaxanthin, astaxanthin, etc.) have molecular lengths that allow themto perfectly span the thickness of an animal cell membrane, with theirend rings sticking out from both the inner and outer surfaces of thecell membrane.

However, it should also be recognized that this same factor (i.e., thealignment of zeaxanthin or lutein in a direction that causes them tostraddle and span an animal cell membrane) makes the difference betweenthe end rings of zeaxanthin, versus lutein, even more important. Asmentioned above, both of the end rings of zeaxanthin have conjugatedelectron clouds that extend into, and cover, parts of both ofzeaxanthin's end rings. Therefore, in zeaxanthin, the conjugatedelectron cloud (which can help absorb and quench UV rays, and oxidativefree radicals), extends and protrudes partway out from both sides of ananimal cell membrane, when a zeaxanthin molecule settles into the cellmembrane.

By contrast, as mentioned above, one of the end rings of lutein has noconjugation, and no electron cloud. Therefore, lutein cannot extend aprotective electron cloud, out beyond one side of the cell membrane.

The perfect end-to-end symmetry of zeaxanthin (compared to the lack ofsymmetry in lutein), and the presence of a conjugated and protectiveelectron cloud over both end rings of zeaxanthin (while lutein has aprotective cloud over only one end ring), are presumed to be the primaryreasons why the human retina prefers zeaxanthin over lutein.

The retina is the thin layer of nerve cells located at the back of theeye, where sight actually begins. When light enters a mammalian eye, itpasses through the cornea (a clear layer on the front of the eye), aclear liquid called aqueous humor (which is thin and watery), a focusinglens (which becomes cloudy, in people with cataracts), and then anotherclear fluid (called vitreous humor, since it has a consistency close togelatin). All of those are clear, and they allow light to pass throughthem, so that the light can reach and activate nerve cells in theretina.

Using “rod and cone” structures that contain light-sensitive chemicals,the nerve cells in the retina convert incoming light, intochemically-driven nerve signals. Those nerve signals are sent to thebrain, where they are processed by the brain to form images and sight.Therefore, the retina plays a crucial role in vision. If the retinadoesn't work properly, neither does vision.

The macula is the most important part of the retina, by far. It is asmall yellowish circle, only about an eighth of an inch wide, located inthe very middle of the retina, covering the exact center of the field ofvision. However, despite its small size, it is crucially important togood vision, because of a factor most people don't realize. The onlypart of the retina that provides fine resolution is the macula, in thecenter of the retina. The rest of the retina provides only coarseresolution.

Most people never notice that fact, because they are accustomed tohaving both of their eyes flit rapidly across moderately wide areas, inways that allow the brain to rapidly assemble a complete field of visionwith good detail and accuracy. However, the human brain has evolved anextraordinarily useful way to speed up its ability to rapidly make senseof huge numbers of incoming nerve impulses. It does so by using fineresolution only in the very center of the retina, and coarse resolutionin the remainder of the retina.

As a simple demonstration of this feature of human vision, if a personcovers up one eye, with a hand or sheet of paper, while looking at apage of text, and then looks through just one eye at a single particularletter printed on the page, it becomes nearly impossible to read any ofthe words directly above or below that letter, in a line of text that isonly three or four lines higher or lower on the page. It is also nearlyimpossible to read any words, through one eye, that are more than aboutan inch to the left or right of the particular letter that is beingstared at. Most people are startled to realize how difficult thatchallenge is, because they never notice that their vision has fineresolution only in the center.

Indeed, the physical structure of the retinas of primates (which evolvedover many millions of years, in ways that helped give primatessubstantially better vision than other classes of mammals) helped createand drive that feature. In most of a human or other primate retina, thecapillaries and other blood vessels that provide blood to the retinalcells (which need large quantities of fresh blood, because they are soactive) are placed on the front side of the retina, where they interferewith incoming light. That interference can be tolerated without harmingvision clarity, because vision is not very clear or high-resolutionanyway, in those parts of the retina. By contrast, in the macula, thestructure and placement of the blood vessels is entirely different. Inthat small region, the blood vessels have moved to the backside of theretina, so that they are positioned behind the layer of nerve cells inthe macula. In that one small portion of the retina, they do notinterfere with the incoming light before it can reach the retina.Therefore, this placement of blood vessels, behind the nerve cells inthe small macular portion of the retina, allows and promotesfine-resolution vision, but only in the very center of the field ofvision.

Because it is the only part of the retina that provides vision with fineresolution, the macula must be healthy, for good vision. If the maculadegenerates, a person will lose the ability to read, drive, recognizefaces, or even be able to walk safely down an unfamiliar sidewalk orhallway.

Loss of vision (up to a point that results in functional blindness ormajor impairments), caused by macular degeneration, happens to hundredsof thousands of people every year. Among the elderly, maculardegeneration is the leading cause of blindness. Furthermore, because ofdemographic and dietary shifts in industrialized nations over the pastdecades (in particular, as the population ages, and as people eat moreprocessed and fatty foods and fewer dark green vegetables), maculardegeneration is becoming even more widespread, at alarming rates. Asbriefly summarized in a newsmagazine, “Eating doughnuts and other fattytreats doubles the risk of going blind later in life” (Shute 2003, whichbriefly summarized the results reported in Seddon et al 2003). Despiteevery warning, many millions of people will continue to eat more andmore fatty treats, and fewer and fewer dark green vegetables.

Studies of the retinas of people who suffer from macular degeneration(including studies on living people, using non-invasive measurements of“macular pigment optical density” (MPOD), as well as chemical studies ofretinas harvested from macular degeneration sufferers who died of othercauses) have made it clear that low levels of macular pigment are strongcorrelated with increased risk of macular degeneration. It is abundantlyclear that people with less-than-normal concentrations of zeaxanthin, inthe macular portions of their retinas, suffer higher risks and rates ofmacular degeneration then people with normal levels of zeaxanthin.

With regard to lutein, there is no clear data, and no clear consensus.Since both pigments normally are found together, in plant sources, it isdifficult to distinguish between them, and it generally has beenpresumed, for nearly two decades, that both pigments are important.However, recent research that has been specifically designed todistinguish between the concentrations and effects of zeaxanthin andlutein has begun to suggest that zeaxanthin plays a more important rolethan lutein, in protecting the eyesight (e.g., Gale et al 2003).

As briefly mentioned above, another crucially important and revealingfact of nature distinguishes zeaxanthin from lutein, in human retinas.It is clear that the human macula contains only zeaxanthin and lutein,as the two pigments that give the macula its distinctive yellowishcolor. However, the macula places those two different carotenoids indifferent locations. It deposits zeaxanthin at highest concentrationsdirectly in the center of the macula, in the most crucial part of themacula. Then, it surrounds that high-concentration zeaxanthin zone inthe center, with a ring of higher lutein concentrations.

There is no sharp dividing line, between zeaxanthin in the center of themacula, and lutein around the edges. Instead, there is a transitionzone, with zeaxanthin concentrations gradually decreasing, and luteinconcentrations gradually increasing, as the distance from the center ofthe macula increases.

This fact about the retina must be considered in view of an importantand well-established fact of nature: lutein is relatively abundant inplant sources, while zeaxanthin is scarce. Lutein is a dominantcarotenoid, which is present in a fairly wide variety of food sources.This dominance apparently arose because the structure of lutein'snon-conjugated end ring allows it to fit, in an ideal manner, intocertain structures in plant cells that are involved in photosynthesis.As a result, even in plants that have unusually high concentrations ofzeaxanthin (such a spinach, kale, etc). there is roughly 20 to 50 timesmore lutein, than zeaxanthin. Therefore, lutein can be obtained muchmore easily and readily than zeaxanthin, and in much higher quantitiesand concentrations, from plant sources in the diet.

Nevertheless, despite the huge imbalance in favor of higher luteinsupplies, the retina somehow obtains and places the highestconcentrations of zeaxanthin directly in the center of the macula, whileit places lutein at high concentrations only around the periphery of azone that has higher zeaxanthin concentrations.

These items of evidence, placed together, strongly indicate that humanretinas have developed and evolved with a notable and substantialpreference for zeaxanthin, over lutein.

In addition, there is yet another important factor which clearlyindicates that the human retina prefers zeaxanthin over lutein. Actingapparently through enzymatic and/or light-triggered reactions that arenot fully understood, the human retina attempts to convert lutein intozeaxanthin. However, the retina cannot convert lutein into the sameisomer of zeaxanthin that exists in the natural diet. The only isomer ofzeaxanthin that is present in dietary sources is the 3R,3′R stereoisomer(also referred to as the R-R isomer, for convenience), which means thatthe “right” (or dextrorotatory, rather than left, or levorotatory)stereoisomer arrangement is present on both of zeaxanthin's two endrings. However, the human retina cannot form the normal R-R isomer, whenit converts lutein into zeaxanthin. Therefore, the retina convertslutein into a different isomer, called meso-zeaxanthin, or S-Rzeaxanthin. Therefore, the presence of the non-dietary S-R (meso) isomerof zeaxanthin, in human retinas, is clear evidence that the human retinais attempting to convert lutein, into zeaxanthin.

In passing, it should be noted that the S-R (meso) isomer of zeaxanthinhas never been shown to exist in any known dietary sources. Although areport from the mid-1980's (Maoka et al 1986) asserted thatmeso-zeaxanthin had been found in certain types of fish, that assertionwas later contradicted by the discovery that alkaline treatment ofcarotenoids (as used by Maoka et al) can convert lutein intomeso-zeaxanthin. Accordingly, the claim that meso-zeaxanthin had beenfound in fish may have been, instead, merely an artifact of thecarotenoid extraction process they used, and meso-zeaxanthin has neverbeen shown to exist in any food sources that humans eat. Its safety, asa food additive for humans (or as a feed additive for poultry orfarm-raised salmon) is not known, and has not been evaluated.Accordingly, any efforts to add meso-zeaxanthin (created by alkalinetreatment of lutein) to any human food source (either as a dietarysupplement, or as a feed additive that is fed to poultry or fish) raiseserious questions as to whether such additives are safe and legal, underthe terms of the United States' Dietary Supplement and Health EducationAct.

Accordingly, the major points discussed above can be briefly summarizedas follows:

-   -   1. Zeaxanthin has been shown to be a better and more potent        anti-oxidant than lutein, in lab tests;    -   2. Zeaxanthin is completely symmetrical, while lutein is not;    -   3. Zeaxanthin is able to extend a “conjugated electron cloud”        (which is useful and protective, since it can absorb UV rays as        well as destructive oxygen free radicals) beyond both sides of a        cell membrane, while lutein can extend that type of protective        electron cloud beyond only one side of a cell membrane.    -   4. Even though lutein is far more abundant in plant sources,        zeaxanthin is deposited at higher concentrations in the        crucially important center of the macula. Lutein is deposited        only at low concentrations in the center of the macula, and at        higher concentrations around the less-important periphery.

At one level of analysis, one might presume that these four factorssuggest two logical conclusions: (i) the macula wants and preferszeaxanthin, over lutein; and, (ii) when the macula cannot obtain enoughzeaxanthin (because zeaxanthin is so scarce in food sources), it willmake up the deficit by using lutein, because of lutein's closestructural similarity to zeaxanthin.

However, that is only one possible analysis, and it appears that no one,prior to the inventor herein, has ever cleanly and concisely assembledall four of those factors, into a fully cohesive, consistent, andpersuasive argument for zeaxanthin. Instead, any analyses of thisinvention must also take into account several additional and equallycompelling facts and factors, which center around the following:

-   -   (i) numerous published reports, in respected and refereed        journals, assert that there is no solid and reliable evidence        that zeaxanthin actually can help protect the retina;    -   (ii) numerous published reports explicitly advise physicians who        treat patients suffering from eye diseases that it is premature        and ill-advised for any physician to instruct patients to begin        taking any unproven and potentially dangerous supplements;    -   (iii) when a large panel of world-class retinal experts was        asked, in 1998, by the National Eye Institute, to list the best        and most promising candidate agents for future research to help        prevent or treat retinal diseases, that entire panel, in its        collective wisdom and expertise, completely omitted both        zeaxanthin and lutein as candidates that should be considered        for research, even though the members of that panel were aware        of both zeaxanthin and lutein and had even published articles on        them prior to 1998; and,    -   (iv) in October 2003, when one of the world's top experts in        treating macular degeneration was informed that one of his        patients was taking zeaxanthin, the physician specifically        advised the patient to stop taking zeaxanthin, since it might        interfere with a different treatment that the physician was        planning to give the patient.

These factors offer powerful evidence that the invention disclosedherein, which rests upon zeaxanthin as the crucial and essentialingredient in multi-component formulations for preventing or treatingeye diseases, is not obvious to those who are truly skilled in the art,and who in fact have devoted their careers to trying to prevent andtreat eye diseases.

This current invention arises from substantial additional readings andresearch into eye health, by the Inventor herein, during the pastseveral years. Despite his realization that zeaxanthin appears to be thecrucial and essential key to good eye health, he continued to carefullystudy and analyze both: (i) hundreds of published reports and productclaims, for literally hundreds of products and ingredients that arebeing sold or touted as being able to benefit eye health, and (ii)hundreds of published articles, on various aspects of eye physiology,anatomy, and structure, and on eye diseases and disorders.

Those readings and research, followed by extensive thought and effortsto synthesize everything he had read on the subject of eye health andeye products, led him to several realizations that are discussed in moredetail below. One of the key realizations can be briefly summarized asfollows: the eye is designed to serve as an interface, between twoentirely different realms of nature (one realm is outside the body,where light begins, and the other realm is inside the body, where sightbegins), and even between two completely different realms of science(the eye must be able to convert physics, in the form of electromagneticradiation, into chemistry, in the form of neurotransmitters and nerveimpulses). The eye can accomplish these results, only by being able tocombine, into a single unit, multiple types of tissues, cells, andstructures (including two different types of clear tissues, twodifferent types of clear liquids, two different types of photoreceptors,and nearly a dozen distinct layers, in and behind the retina).

One of the factors that enabled and promoted the evolution anddevelopment of an extraordinary level of complexity, in human eyes,relates to the fact that carotenoids are multi-functional agents, andcan perform more than just one role or task. In addition to being highlyeffective in absorbing ultraviolet light, they are also highly effectivein quenching oxidative free radicals.

However, the multifunctionality of carotenoids doesn't stop there. Theyalso have mild yet potentially helpful and useful ability to control andreduce inflammation. This is a crucial benefit, in many types of eyedisorders, since inflammation can lead to severe adverse results, if itlasts for a number of days, weeks, or months in succession. Onemechanism for potentially serious damage to the eyesight, cause byinflammation, arises from the effects of increased fluid pressuresinside the eyeball. This fluid pressure will be imposed on the exteriorsurfaces of the capillaries that provide blood to the retina. Sincecapillary walls must be extremely thin (in order to promote rapidexchange of oxygen, nutrients, and metabolites), they cannot resist andpush back against elevated fluid pressures on their exterior walls. As aresult, elevated pressures inside the eye, if they arise as a result ofinflammation after an injury or infection, can act in a mannercomparable to a severe and accelerated case of glaucoma (a disease thatalso involves elevated fluid pressures inside the eye, which causesreduced blood flow through the retinal capillaries, and which can causesevere and permanent damage to retinal nerve cells). Therefore, theability of certain carotenoids to help control and reduce inflammationcan become crucially important, and extremely helpful, in response toinjuries, infections, or other events that can trigger inflammation ofone or more types of eye tissues.

Similarly, carotenoids also have a mild yet potentially useful andhelpful level of activity in preventing and reducing “sclerosis”. Thisterm refers to hardening, stiffening, and loss of flexibility (forexample, arteriosclerosis refers to hardening of the arteries, andatherosclerosis is a related process in which the insides of thearteries become coated with cholesterol or other fatty deposits). In theeyes, sclerosis and loss of flexibility (which can also arise whensubstantial quantities of drusin, lipofuscin, and other debrisaccumulate) can adversely affect certain membranes, such as the Bruch'smembrane, which is a crucially important layer in the back of the eye,behind the retina. Therefore, the ability of carotenoids to help preventand reduce sclerosis is yet another way in which carotenoids can helpprotect eye health and good vision.

After the inventor herein had read about and recognized those additionalroles of carotenoids, he then began to actively notice still moredifferent roles and activities that are being played by carotenoids. Acomplete list must include (but is not limited to) the following:

-   -   (1) Carotenoids have mild yet potentially useful levels of        activity in controlling and regulating angiogenesis (i.e., the        formation of new blood vessels, which can lead to extremely        severe problems in the wet or exudative form of macular        degeneration).    -   (2) Carotenoids have mild yet potentially useful levels of        activity in helping to modulate and regulate the functioning of        mitochondria, which are crucial to oxygen usage, respiration,        and energy utilization by a cell.    -   (3) Carotenoids have mild yet potentially useful levels of        activity in helping to modulate and regulate apoptosis, a form        of “programmed cell death,” in which cells that receive certain        signals or that enter into certain states trigger a process that        leads to fairly rapid death of the cell. This process        effectively allows other specialized cells (glial cells in the        nervous sytem, and immune cells in the remainder of the body) to        clean up and remove the cell debris, so that the system in that        locality can go back to functioning properly, without being        hindered by a lingering cell that is crippled, useless, and a        drain on resources.    -   (4) Carotenoids have mild yet potentially useful levels of        activity in helping to regulate and control certain types of        actions and responses of the immune system.

It must be kept in mind that this brief listing (immediately above) offour different “peripheral” activities, by carotenoids, must be added totwo other peripheral activities (i.e., modulation of inflammatoryresponses, and modulation of sclerotic hardening), and all six of thoseactivities must then be added to the two “primary” activities ofcarotenoids (i.e., absorbing and quenching destructive ultravioletphotons, and absorbing and quenching destructive oxygen free radicals).

There are also various other scientific reasons for believing that (i)many eye disorders are multi-factorial, and (ii) the best treatments orpreventive agents for such disorders will also be multi-factorial. Thesefactors are highly complex, and involve, for example: (i) the fact thatinflammation and immune responses can both create oxygen free radicalsand “reactive oxygen species”; (ii) various types of signalling pathwaysthat cells use, to effectively communicate with each other; and (iii)the crucial involvement of mitochondria in many of these processes, andin processed involving apoptosis and programmed or signalled cell death.

Upon reading and realizing that carotenoids must be able to perform twoabsolutely crucial primary and central roles (neutralizing UV photonsand free radicals), while also being called upon to perform at least sixknown secondary and peripheral activities, the inventor herein graduallyreached several conclusions about carotenoids in human eyes. Those twoconclusions can be summarized as follows:

-   -   1. If carotenoids are being asked to perform eight different        tasks (and possibly even more) in a single eye, they are more        likely to become “stretched thin”, and unable to adequately        handle all of those tasks simultaneously, than other molecules        that only need to perform fewer numbers of tasks;    -   2. Research reports have indeed shown that people who are        suffering from certain types of eye problems do indeed suffer        from low carotenoid concentrations in their blood (as shown by        tests on blood serum) and/or their eyes (as shown by inadequate        levels of zeaxanthin in people with macular degeneration, and        reduced zeaxanthin densities in the lenses of people suffering        from cataracts);    -   3. If any or all of the “secondary demands” that are being        imposed on carotenoids in the eyes can be reduced, by ingesting        or administering other nutrients that can provide a balanced        regimen that will help address and satisfy those secondary        demands, then any newly-arriving carotenoids will be more likely        to actually arrive at locations where they can carry out their        essential primary roles, and provide the most overall benefit.

Accordingly, over a span of time that allowed careful consideration andadditional readings on related subjects, this line of logic and analysisbegan to suggest, more and more persuasively, that well-balancedeye-care preparations would be able to do the greatest possible good, inprotecting or restoring the extraordinarily complex needs of human eyes,if those formulations contain both: (i) zeaxanthin, as the ideal,symmetric, fully-conjugated carotenoid that has been fully optimized (bymillions of years of evolution) for interacting in beenficial ways withanimal cells and animal cell membranes; and, (ii) one, two, or moreadditional ocular-active nutrients that can directly and efficientlyaddress and correct any one or more “secondary demands”, which otherwisewill tend to “siphon off” part of any zeaxanthin that reaches the eye.

Viewed from another perspective, zeaxanthin can be regarded as a form of“buffer”, in a system that is constantly trying to sustain anequilibrium (which is usually called “homeostasis”, when livingbiological systems are involved). Like buffer compounds, carotenoids canrespond to whatever is added to (or imposed upon) the system, in a waythat usually will help the system move back toward its equilibrium (alsoreferred to as the “set-point” of the system). However, it must also berecognized that if the outer limits of the buffering capacity of acertain buffer compound has been reached in a certain system, additionof even a slight quantity of additional acid or alkali can cause majorswings and unheavals, in the system. In an analogous manner, if thecarotenoids in a human eye are “stretched thin”, by a combination ofmultiple competing demands, all demanding responses at the same time,then the overall protective system can fail, leading to a variety ofstresses, problems, and damage, all occurring at once, and actingtogether in ways that are suggested by phrases such as vicious circle,witch's brew, etc.

Subsequently, as the inventor pondered various approaches to developingand optimizing ways to respond to complicated and intertwined problemsthat lead to (or are caused by) complex, difficult, and oftenintractable ocular diseases and disorders (which lead to serious visualimpairment, functional blindness, or complete blindness in millions ofpeople every year, despite the best efforts of thousands of doctors andresearchers), he eventually arrived at a complex intersection, whereroughly half a dozen distinct themes all converge and cross each other.Briefly, those themes include the following:

-   -   (i) Using nature and evolution as the best examples and the best        instructors, many and probably most of the best candidate        ocular-active nutrients are likely to be derived from plants;    -   (ii) In the same way and for the same reasons that occur in        plants, many and probably most of the best candidate        ocular-active nutrients are likely to have strong or even        exclusive specificity for certain stereoisomers, and racemic        mixtures created by non-specific chemical synthesis should be        avoided wherever possible;    -   (iii) Despite the dominance of plant nutrients as offering the        best candidates overall, humans evolved most efficiently as        omnivores, and diversity should be recognized, respected, and        valued. Accordingly, animal sources may well offer one or two        ocular-active nutrients that may provide good and useful        complements, when added to best-candidate plant nutrients for        eye health; and,    -   (iv) after a list has been developed that contains the best        candidates from the realm of naturally-occurring ocular-active        nutrients, the final step is to make good, shrwed, intelligent        use of technology, to get those natural products properly        stored, packaged, and delivered. In this context, appropriate        technological steps can include, for example: (i) the use of        oily carrier substances, to deliver active agents (including        carotenoids) that are naturally oil-soluble; (ii) the use of        timed-release and/or sustained-release technology, to establish        sustained and lasting increased blood concentrations of any        compounds that otherwise disappear rapidly from the gut or from        circulating blood; and, (iii) the use of various types of        bioavailability enhancers (such as bile salts, phospholipids, or        pancreatic lipase), to increase the untake of oily compounds        through the intestinal walls, and into circulating blood.

After extensive thought, reading, research, and discussions concerningvarious different factors listed above, the inventor herein has reacheda point where it is now time to convert these concepts and ideas intodetailed and specific tests, which must be woven together into aconsistent and cohesive program that is planned and organized to leaddirectly to a specific outcome that can be clearly envisioned anddescribed at this time, even though the screening tests have not yetbeen commenced that will identify those specific agents that willperform most potently, synergistically, and beneficially, when combinedwith zeaxanthin.

Accordingly, one object of this invention is to disclose multi-componentorally-ingestible formulations for protecting eye health in mammals(including humans), which contain zeaxanthin as an essential andcritical ingredient, and which also contain at least two or more otheragents that have been proven, in tests on humans or other primates, toact in a synergistic and potentiating manner with zeaxanthin, to provideimproved efficacy in preventing or treating eye diseases.

Another object of this invention is to disclose a focused method ofapproach that will be able to clearly identify ocular-active nutrientsthat, when added to zeaxanthin, will be able to improved the efficacy ofzeaxanthin in preventing or treating eye diseases.

Another object of this invention is to disclose a method (which hasintertwined aspects of both scientific research, and a method of doingbusiness) that will sort through hundreds of competing and confusingproducts that are accompanied by unsupported and unreliable advertisingand marketing claims, and which will provide (i) elderly people who aresuffering from vision loss; (ii) their families, caregivers, andinsurance companies; and, (iii) government and charitable institutionsthat will be forced to bear the brunt of the costs of caring formillions of elderly people who are at severe risk of becomingfunctionally blind, with genuinely useful and reliable products andinformation that will be truly effective in preventing an epidemic ofblindness, which otherwise will occur as the population ages, and as thelong-terms effects of unhealthy high-fat diets gradually take their tollon the aging populace.

These and other objects of the invention will become more apparent,through the following summary, description, and claims.

SUMMARY OF THE INVENTION

A process is disclosed for identifying ocular-active nutrients that willinteract in a synergistic and potentiating manner with a carotenoidcalled zeaxanthin, to provide better and more effective protection, foreye health, than can be provided by zeaxanthin alone. Product-by-processcombinations of such ocular-active nutrients that are identified asoffering especially potent and useful eye health benefits, when combinedwith zeaxanthin, are also disclosed.

Eight categories of candidate ocular-active nutrients are identifiedherein. These eight categories can be summarized as follows:

-   -   (1) Lipoic acid, preferably in the form of a purified or        enriched naturally occurring “R” (dextrorotatory) stereoisomer        rather than a racemic mixture.    -   (2) At least one omega-3 fatty acid, such as docoso-hexaenoic        acid (commonly referred to as DHA) or one of its linolenic acid        precursors, preferably obtained from a natural source such as        fish oil or marine algae.    -   (3) Various plant-derived compounds that are referred to by        various scientists as flavonoids, bioflavonoids, anthocyanins,        plant polyphenolics, or phytonutrients. These compounds include        extracts from bilberry, grapeseed, or green tea, as well as soy        isoflavones, quercetin, genestein, diazedem, fisetin, luteolin,        resveretrol, and pycogenol.    -   (4) Taurine, the common name for amino-ethane-sulfonic acid, a        “conditionally essential nutrient” that is present in milk and        various tissue types.    -   (5) Carnitine, a sulfur-containing amino acid (not one of the 20        primary amino acids used in protein synthesis) that is formed in        the liver and elsewhere, and various esters and/or precursors of        carnitine, such as acetyl-L-carnitine.    -   (6) An enzyme cofactor known as Coenzyme-Q10, which is a known        anti-oxidant that provides energy-related support to        mitochondria. In some situations, it can help prevent or reduce        a process called “apoptosis” that leads to a type of programmed        cell death.    -   (7) Carnosine, a di-peptide formed from alanine and histidine,        which can prevent reactive aldehydes from causing unwanted        glycosylation or crosslinking of proteins.    -   (8) Nutrients that can stimulate the production or metabolism of        glutathione, a tri-peptide that helps cells eliminate waste        products. One such agent is N-acetyl cysteine, an ester that is        metabolized to release the cysteine, the sulfur-containing amino        acid in the center of glutathione.

In addition to those eight categories (none of which were tested duringthe AREDS-1 trial in the 1990's), three classes of compounds that weretested in the AREDS-1 trial also may merit attention. Two of thosecategories include tocopherol compounds, such as alpha-tocopherol(vitamin E), and ascorbic acid (vitamin C) or a salt or ester thereof,such as ascorbyl palmitate. The third category includes zinc. Whenvitamins C and E (as well as beta-carotene) were combined at highdosages, they offered a low and weak level of protection against maculardegeneration, in some but not all of the patient categories, in theAREDS-1 trial. Similarly, zinc at very high dosages (80 mg/day), byitself, offered a low and weak level of protection in some categories ofpatients. When vitamins A/C/E and zinc were combined, the level ofprotection increased, especially among late-stage macular degenerationsufferers.

Accordingly, the results and findings of the AREDS-1 trial are notregarded as strong or compelling, when compared with the potentialbenefits of zeaxanthin, and in recent years it also has become clearthat high dosages of vitamin A or its precursor, beta carotene, offerlittle or no serious hope for providing any significant protectionagainst macular degeneration, or any other serious eye disorders amongpeople who receive minimal baseline levels of vitamin A. However,various general and specific benefits of vitamins C and E, and of zinc,are well known and solidly proven, especially among elderly people andpeople with poor diets. Therefore, vitamins C and E, and zinc, remain ofinterest, and they will be tested (possibly in the form of the completeAREDS formulation, which is commercially available) in combination withzeaxanthin, to determine whether they can provide a synergistic benefitthat will improve substantially on the results that can be provided byzeaxanthin alone.

To evaluate and rank the efficacy and synergistic activities of thesecandidate ocular-active nutrients, selected tests that have been chosento accommodate various animal models (including a number of animalmodels described below) can be used. Each type of animal model canprovide different types of data, which will relate to certain componentsof the eye and certain known ocular disorders. Researchers who areexperienced in designing and carrying out such tests understand thetypes of data that can be gathered from each such test, and from eachtype of animal species that is well-suited for use in a particular typeof test. Accordingly, testing regimens with targeted data-gatheringmethods can be developed, to gather specific types of data that willindicate which ocular-active nutrients listed above are likely to havethe most valuable and beneficial effects, when combined with zeaxanthinand then tested in human clinical trials.

Based on the results of the animal tests, candidate formulations can betested in clinical trials on humans who are suffering from various typesof eye disorders. Testing regimens are known, and can be designed byskilled experts, for use with nearly any type of eye disorder. At leastsome types of tests can be designed to speed up the gathering of usefuldata, when testing patients suffering from diseases that graduallymanifest over a span of multiple years. This type of accelerated datagathering can be enabled by various approaches, such as by focusing onselected patients who, at the point in time when they will be tested,are entering or progressing through certain stages that involveaccelerated and rapid degeneration and loss of vision acuity. Oneexample, among most patients who suffer from the dry form of maculardegeneration, involves an intermediate stage called “geographicatrophy”, which occurs when distinct patches of degeneration in oraround the macula become clearly visible, in certain types of diagnosticphotographs. It is not yet known which specific ocular-active nutrientsin the candidate categories listed above will act in the most potent,effective, and beneficial synergistic manner, when combined withzeaxanthin. What is known, instead, is that the uncontrolled andunsupported profusion of eye-care nutritional products, all with theirown competing and confusing claims designed to sell products now (ratherthan support research for the future), is not working adequately, andwill not work adequately in the future, unless something happens thatalters the landscape in an important and useful manner. Patients cannotbe sure what to take, physicians cannot be sure what to recommend, andthe largest and most powerful companies that sell eye care nutrientshave shown, by their actions, that they apparently are determined tominimize zeaxanthin in their plans and products, rather than recognizingits crucial role at the center of the macula, and as the foundation andthe single most important ingredient in any nutrient formula that willbe truly effective and useful in protecting eye health and good vision.

The current system does not offer any realistic hope of preventingdozens or even hundreds of millions of cases of avoidable blindness,which will occur around the world over the next 20 years unless a betterapproach can be found than the approach that has been adopted and usedso far by the largest companies that sell eye care products, and by theNational Eye Institute. Accordingly, the testing and screening approachdisclosed herein should be regarded as a process, and the synergisticcompositions that will result will be product-by-process compositions.Such product-by-process compositions should be evaluated, not bypointing out that certain items of prior art have been published on eachof the candidate nutrients listed above, but by comparing the testingand screening method disclosed herein, which will treat zeaxanthin as anessential “anchor” ingredient that will be included in all formulationsthat will result from this approach, against: (i) the research programsand eye-care nutritional products that have been created by othercompanies that sell such products; and, (ii) the actions of the NationalEye Institute, which has stated in communications to the inventor hereinthat it is planning to deliberately exclude zeaxanthin from theso-called “AREDS-2” trial, and focus on lutein instead.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 (which is prior art) depicts the chemical structures ofzeaxanthin and lutein (with an arrow pointing out the misplacednon-conjugated double bond in one end ring of lutein), and beta-carotene(a similar carotenoid that does not contain any oxygen molecules orhydroxy groups).

FIG. 2 (which is prior art) comprises FIGS. 2A, 2B, and 2C. FIG. 2Adepicts the bilayer structure of an animal cell membrane, formed by tworows of phospho-lipids having water-soluble phosphate “heads”, andoil-soluble lipid “tails”. FIG. 2A depicts the way a molecule ofbeta-carotene (which has no oxygen atoms or hydroxy groups) will aligneditself entirely within the oily interior of a cell membrane. FIG. 2Bdepicts how molecules of zeaxanthin and lutein will align themselves to“span” or “straddle” a cell membrane, in a way that causes their endrings and hydroxy groups to protrude and extend out, beyond the cellmembrane's outer and inner surfaces.

DETAILED DESCRIPTION

As briefly summarized above, this invention relates to “ocular-activenutrients” that can act in a synergistic and potentiating manner withzeaxanthin, to protect and/or restore eye health and good vision to adegree that rises substantially above the levels of benefit that can beprovided by zeaxanthin alone.

Several points of terminology need to be addressed, before describingthe testing and screening method, and the categories of candidatenutrients, in more detail.

Ocular relates to the eye, and terms such as ocular-active can be usedinterchangeably with other terms such as ophthalmic, eye-related,vision-related, etc.

The term nutrients, as used herein, refers to compounds that are foundin the normal human diet. Under the various laws that have been passedto regulate foods and drugs, nutrients that are present in normal humandiets are usually covered by the laws and rules of the U.S. DietarySupplement Health and Education Act. By contrast, drugs andpharmaceuticals that are not found in the normal diet are regulatedseparately, under different statues and rules. However, as mentionedbelow, it should also be recognized that some nutrients found in thenormal diet can be regarded and regulated as drugs or pharmaceuticals,if (and to the extent) they are prescribed by physicians to treatspecific and diagnosed medical conditions.

Ocular-active nutrients, as used herein, refers to and is limited tocompounds developed for oral ingestion, to provide active, substantial,and measurable benefits for one or more aspects of eye health or visionquality. Although some of these nutrients may also be useful (and indeedmight have accelerated effects) if administered by other means (such asby intravenous or intraocular injection), all claims herein are limitedto nutrient formulations that are intended to be ingested orally. Thisis deemed to be the relevant field of art and usage, and published arton other, different types of formulations (such as, for example,injectable drugs) are not deemed to be relevant herein.

The major use for orally-ingestible ocular-active nutrients, asdiscussed herein, is to protect or treat human eyes, and vision.However, if desired, such formulations may also be used to prevent orcorrect eye-related problems in other mammalian species, such as toprevent cataracts or retinopathies in dogs. The combined formulations ofthis invention can be in the form of pharmaceutical preparations,dietary supplements (also referred to interchangeably as nutritionalsupplements), or foodstuffs.

Pharmaceutical preparations (which can be prescription-only,over-the-counter, or any combination of the two) normally are used totreat known and already-existing problems, while dietary supplements(also referred to interchangeably herein as nutritional supplements)normally are used to sustain a condition of good health. While there isno clear dividing line between pharmaceutical preparations versusdietary supplements (for example, treating physicians often recommenddietary supplements to patients who are suffering from specificdiagnosed problems), a practical difference nevertheless exists betweenthe two categories. This arises from the fact that pharmaceuticalpreparations usually contain higher dosages of active agents, thandietary supplements. Accordingly, for purposes of discussion anddescription herein, terms such as “pharmaceutical preparations” and“therapeutic dosages” are deemed to include any combinations ofocular-active nutrients, as discussed herein, that contain at least 3milligrams (mg) of zeaxanthin, either as a unitary dosage, or as arecommended daily dosage. Preferred therapeutic dosages for mostpatients who are suffering from diagnosed eye disorders usually willcomprise 10 or more mg of zeaxanthin per day.

Dietary (nutritional) supplements generally comprise formulations andpreparations that are designed to be taken by people who wish to sustaina condition of good health, or at least to prevent any furtherdeterioration of their health, regardless of whether they have beendiagnosed with a particular disorder by a physician. Accordingly,dietary supplements they usually have unitary and/or daily dosages thatare within a range that is (i) higher than the minimal quantities (oftencalled “trace amounts”) that are contained in naturally occurring foods,but (ii) lower than the therapeutic dosages that are provided by drugsand pharmaceuticals that are used to treat known medical problems.Accordingly, for purposes of discussion and description herein, dietary(nutritional) supplements are deemed to include preparations thatcontain at least about 0.5 mg zeaxanthin, as either a unitary dosage, oras a recommended daily dosage.

As mentioned above, the categories of pharmaceutical preparations anddietary (nutritional) supplements overlap, and there is no specificupper limit for dosages that would cause a dietary (nutritional)supplement to be reclassified as a pharmaceutical preparation. Safetydata that was gathered on zeaxanthin, using high-dosage tests involvingrats, indicated a “no adverse effect limit” (NOAEL) level of at least1200 mg/day. These data were disclosed in a “75-day PremarketNotification” for zeaxanthin, which was submitted to the U.S. Food andDrug Administration (FDA) by Roche Vitamins, Inc. (the only company thatis currently manufacturing the R-R dietary isomer of zeaxanthin, forhuman consumption), and which was opened for public inspection by theFDA in June 2001 under docket number 95S-0316. In addition, small-scaletests involving human volunteers indicated that dosages of zeaxanthin ina range of 50 to 80 mg/day appear to be entirely safe, and wereeffective in reducing a person's risk and severity of sunburn, whensmall areas of skin were exposed to controlled dosages of high-intensityultraviolet radiation from a medical-grade UV lamp. These high dosagesof zeaxanthin also succeeded in creating slightly reddish skin tones,which turned a darker brown or bronze color that completely resembled ahealthy tan, when subsequently exposed to the sun. Accordingly, peoplewho want tans, or who are planning to go on a vacation or other tripthat will involve exposure to abnormally high levels of sunlight, maytake large quantities of zeaxanthin (up to or even exceeding 100mg/day), to help them avoid sunburn and obtain a deeper tanned color ontheir skin. Such use, even at very high quantities, would be regarded astaking a dietary supplement rather than a pharmaceutical, and suchdosages would still remain far below the NOAEL levels that weredetermined by animal tests.

On the subject of unit dosages and daily dosages, unit dosage formsinvolve discrete units. The most commmon forms are capsules (which usean encapsulating material), tablets (which use compressible bindermaterials), and various types of “hybrid” pills that use encapsulatingmaterials as well as compressible binders (usually called caplets,coated tablets, etc). Other types of unit dosages can also be providedby other means, such as sealed plastic pouches containing measuredamounts of a powder or liquid that is to be added to a food or drink.

Daily dosage forms can include unitary dosage forms (such as tablets orcapsules, which normally are accompanied by a recommendation to take aspecified number of pills per day to achieve a recommended dailydosage). Daily dosage forms also can include liquids, powders, orsimilar preparations, which usually are accompanied by instructionsconcerning a certain volume, weight, or other quantity that should beingested each day to achieve a recommended daily dosage.

It should also be noted that unit dosages can be provided in the form ofcapsules that will contain oily carrier materials, such as a vegetableoil. This can enhance the uptake and bioavailability of zeaxanthin,vitamin E, and various other oil-soluble nutrients disclosed herein. Ifdesired, such oily carriers can also be formulated to carrymicroencapsulated beadlets or other preparations, which can containwater-soluble nutrients or any other components that are easier tohandle if isolated or otherwise coated in that manner.

Another class of compounds that can contain zeaxanthin combined withother ocular-active agents is referred to herein by the term“foodstuffs”. This broad industry term includes compounds that aredesigned to be eaten as a food or drink, having enough volume and bulkto help satisfy an appetite or thirst (as distinct from a tablet,capsule, or other low-volume drug-type preparation). Foodstuffs can becomplete and ready to eat (such as snack foods, energy or nutrition barsor mixes, or desserts, or beverages that are sold in cans, bottles, orpouches, etc.); they can require cooking, mixing, or other preparation(such as frozen or refrigerated snacks or entrees, soups or other foodssold in cans or pouches, cooking ingredients, drink mixes, etc.); or,they can involve any combination of or midway point between thosecategories (such as peanut butter, cheese, vegetable dips, crackerspreads, etc.). They also can be in the form of condiments (such asketchup, sauces, butter, margarine, etc.), flavoring or coloringadditives, or any other preparations that are designed and intended tobe added to foods or beverages, or otherwise eaten or drunk as a food orbeverage.

In order to be covered by this invention, any such foodstuff mustcontain zeaxanthin and at least two or more other ocular-activenutrients, not merely as naturally-occurring ingredients in one of thefruit, vegetable, or other materials used to make the foodstuff, but asadditives that were deliberately added to the foodstuff, in a quantityintended to provide ocular benefits to consumers. In most cases, thistype of intent will be made clear and explicit by labelling informationon packaging, advertising, or other marketing materials that advertise,enclose, or otherwise accompany the foodstuff, which will claim orsuggest that an ocular benefit can be provided by the foodstuff or theadditives therein. Advertising and labelling is an essential part ofidentifying and marketing foodstuffs having special health-relatedbenefits, since the additional costs of such agents cannot be justifiedunless consumers know about the added benefits and are therefore willingpay a correspondingly higher price for products containing them.

The benefits of ocular-active combinations as disclosed herein mayinclude preventing, treating, or reducing the risks of any one or moreeye diseases, injuries, or infections or other eye-related and/orvision-related problems. Such eye-related or vision-related problemsinclude, for example, retinal problems such as macular degeneration,retinitis pigmentosa, and diabetic or other retinopathies; lens-relatedproblems, such as cataracts (including cataracts relating to diabetes);fluid-related problems, such as glaucoma, “dry eye” syndrome, tearingproblems, etc; problems related to hypersensitivity to light, as occurin people with albinism, or who suffer from headaches, epilepticseizures, or other disorders when exposed to certain types of light; andundesired effects or problems arising from injury or infection, or froma surgical or medical procedure that directly affects one or both eyesof a patient or animal (such as a vitrectomy, repair of a torn ordetached retina, laser coagulation using verteporfin, etc.). These andvarious other eye-related disorders are known to ophthalmologists andother specialists.

While there is no specific reason to believe the treatments herein canprevent, retard, or reverse focusing problems that are normallycorrected by glasses (near-sightedness, far-sightedness, orastigmatism), such focusing problems may be aggravated and increased, inat least some patients, by other types of stress or damage imposed onthe eye. As an illustration of this principle, eye-related disordersfrequently are accompanied (and brought to the attention of a patient orphysician) by unusually rapid changes in the corrective strengths thatmust be provided by eyeglasses or contact lenses. Accordingly, byestablishing better, more stable, and healthier overall conditions inthe eye, the treatments herein may be able to help retard the onset of,or reduce the need for, lens correction.

It also should be noted that corrective lenses (including bifocallenses, etc.) are the standard treatment for presbyopia, which refers tothe decline in vision acuity that, in most people, commences oraccelerates in middle age. It is believed and anticipated that, in atleast some patients, by improving the general health of the eyes, byreducing oxidative damage within the eyes, and by reducing stressesimposed on various components of the eyes, the nutrient formulations ofthis invention can help delay the onset of presbyopia, and/or reduce itsseverity, especially if taken over a span of years.

As used herein, terms such as treat, treatment, therapy, or therapeuticare used broadly, and include the ingestion or administration ofpharmaceutical preparations, dietary or nutritional supplements, orfoodstuffs with additives as disclosed herein, in an effort to respondto an existing and known ocular disorder (which can include a disease,injury, infection, etc.). Such treatments may retard or delay, fully orpartially reverse, or otherwise ameliorate, lessen, or benefit a knownocular disorder. Such problems, when they arise, may be revealed by anophthalmic examination, vision test, or other medical examination, orthey may simply become apparent and troublesome to a sufferer (such as anoticeable loss of clear vision). Such disorders may become known, eventhough the sufferer or a treating physician may not have an accuratediagnosis and may simply be aware that something is wrong with either orboth eyes or the vision of the sufferer.

As used herein, terms such as preventing or prophylaxis also are usedbroadly, and include the ingestion of pharmaceutical preparations,dietary or nutritional supplements, or foodstuffs with additives, either(i) to sustain a general state of good health and/or good vision, and/orto reduce a general risk of health or vision problems, in a mannercomparable to taking vitamins; or, (ii) in a manner that is intended toreduce a known elevated risk of one or more ocular diseases ordisorders, by someone with a family or personal history of a disease ordisorder, a known or suspected genetic defect, or some other factor thatindicates an elevated risk of one or more ocular disorders.

Just as there is no clear dividing line between vitamins and drugs (forexamle, a vitamin becomes a drug when it is used to treat someonesuffering from a known vitamin deficiency), there is no clear dividingline between preventive versus therapeutic usage of ocular-activenutrients as discussed herein. As an example, if someone who isrelatively young suffers from a known genetic defect that will affecthis or her vision later in life, and if that person begins to regularlytake an ocular nutrient formulation before any specific degenerationbecomes apparent, then such usage by that person can be classifiedeither as preventive (since the nutrients are being taken to prevent,delay, or reduce problems that have not yet arisen), or therapeutic(since the nutrients are being taken to treat a known genetic defectthat already exists).

Accordingly, while it is useful to bear in mind that this inventionrelates to both pharmaceutical preparations (intended for treating knownproblems, and typically involving high dosages) and dietary/nutritionalsupplements (intended to sustain eye health, and commonly but notnecessarily involving lower dosages), those two categories sometimesoverlap and/or merge with each other, and are not entirely separate anddistinct from each other. It should also be recognized that the categoryof foodstuffs containing ocular-active additives, as described above,normally will fall within the category of dietary or nutritionalsupplements, but may be regarded as pharmaceutical and therapeutic, wheningested by someone who is suffering from a known ocular problem.

While it is not claimed that any one particular ocular-activeformulation can be used to effectively treat all eye-related disorders,the following points are asserted by the inventor:

-   -   (1) Because of the central role that zeaxanthin plays in the        eye, in absorbing and quenching ultraviolet radiation as well as        oxidative free radicals, nutrient formulations that contain        zeaxanthin along with other ocular-active nutrients are highly        likely to be substantially more effective, in treating a wide        variety of eye disorders, than comparable formulations that do        not contain zeaxanthin; and,    -   (2) Any well-planned, useful, and publicly and socially helpful        research project that is intended to help create or evaluate a        useful and beneficial ocular-active nutrient formulation must be        designed to evaluate candidate agents, not in isolation, but in        combination with zeaxanthin, since zeaxanthin will be an        essential ingredient in any optimal or near-optimal nutrient        formulation that will truly benefit and protect the vision of as        many people as possible.        Animal Models for Initial Testing

As mentioned above, at least five different and distinct animal modelsare known, for testing candidate ocular-active nutrients. These modelsinclude the following:

1. Mice and Rats, Including “Knockout” Mice

Mice and rats are very widely used in research on small animals, and ahuge foundation of information, species-specific biomolecules (includinggene promoter sequences, gene coding sequences, monoclonal antibodies,etc.) and specialized strains have been developed for genetic work withmice. Gateways that can be used to access mouse genetic information arefreely available on websites such as www.informatics.jax.org andwww.ncbi.nlm.nih.gov/genome/seq/MmHome.html. Although the correspondinggenetic information on rats is somewhat smaller, it is still enormousand quite useful, and can be accessed through websites such ashttp://rgd.mcw.edu, http://ratmap.gen.gu.se, andwww.hgsc.bcm.tmc.edu/projects/rat.

This genetic information can be put to good use, because a growingnumber of gene defects have been and are being correlated with known eyedisorders. These genes can be discovered by any of several procedures.For example, research revealed that many people who suffer fromStargardt's disease, which causes severe vision impairment, have adefective protein known as the Rim protein, which normally functions asan ATP-binding cassette (ABC) transporter gene, in rod outer segmentdiscs, in mammalian retinas. Additional research on that protein (andthe gene which encodes that protein) led to identification of a genecalled the ABCR gene, as the specific defect that leads to the defectiveRim protein in people who suffer from Stargardt's disease.

After the human ABCR gene was identified as a causative factor inStargardt's disease, a “homologous” ABCR gene in mice was located, whichencodes the mouse version of the Rim protein. The exact DNA sequence ofthe mouse ABCR gene was determined, and researchers then used geneticengineering techniques to create mutant mice with “knockout” ABCR genesthat are no longer properly functional. These mutant mice, with“knockout” ABCR genes and the mouse equivalent of Stargardt's disease,are described in articles such as Weng et al 1999 and Mata et al 2000.Their descendants suffer from severe visual impairment, which growsgradually worse as certain waste metabolites gradually accumulate withinthe retinas. Therefore, the descendants of these knockout mice offeruseful animal models, for testing candidate nutrients that may be ableto help slow down the gradual loss of vision in such mice.

This example, focusing on the ABCR gene that was rendered nonfunctionalin a colony of “knockout” mice, is just one of numerous examples of howrapid progress is being made, by using and comparing gene sequenceinformation that has already been gathered as part of the human genomeproject, the mouse genome project, and the rat genome project. Dozens oreven hundreds of genes that express specific proteins involved in eyestructures and/or vision processing have been identified, and the onlythings that limit how quickly and effectively that genetic informationcan be used are money, and resources.

Four presumptions apply to such research: (1) every structural proteinthat is present in any eye structure, and every enzymatic protein thatis involved in any step in vision processing in the eyes, is presentwithin the eyes for a good reason, and plays some useful and necessaryrole in vision; (2) a gene defect that renders any such proteinnonfunctional will very likely lead to some type of identifiable andpotentially important eye disorder; (3) once any such genetic defect hasbeen identified, either in humans or in mice or rats, colonies of labanimals which will carry that genetic defect can be created and/orraised; and, (4) any such colony can provide an animal model, which canhelp researchers evaluate and rank the ability of various candidatenutrients or other treatments to overcome the problem that is caused oraggravated by that particular defective protein, in that particularanimal model.

Accordingly, genetic analysis and research, including research involvingmice or rat colonies having “knockout” genes that are correlated withspecific vision disorders, offer extremely powerful tools, and canprovide an effectively unlimited number and range of specific targeted“models” that can help researchers test candidate nutrients, to evaluatewhether any nutrient or nutrient combination can act synergisticallywith zeaxanthin, to help prevent or treat one or more specific types ofocular disorders.

2. Use of Agents to Increase Carotenoid Uptake in Rodents

When carrying out vision-related research on mice or rats, it must benoted that most rodents are prey rather than predators, and almost nevergo out into direct sunlight in the middle of the day, since that wouldmake them highly vulnerable to predators. Accordingly, rodents did notevolve with any need for carotenoids to help protect them against UVradiation. Therefore, rodents generally do not metabolize carotenoids inways comparable to humans, and they tend to make relatively poor modelsfor studying the uptake or effects of carotenoids.

However, various manipulations can be used to increase carotenoid uptakein rats and other rodents. As one example, if relatively highconcentrations of bile salts or other compounds that help solubilizefatty compounds are added to the diets of mice or rats, the animals willtransport higher quantities of carotenoids through the intestinal wallsand into circulating blood, which will lead to greater rates andconcentrations of tissue deposition. Therefore, by feeding special dietsto mice or rats, various types of research involving zeaxanthin (orother carotenoids) can be carried out in these animals.

It should also be recognized that research which directly uses andincludes zeaxanthin will not always be necessary, to do research on miceor rats that can help evaluate and rank candidate nutrients that may beable to work synergistically with zeaxanthin. Instead, the benefits ofworking with mice or rats usually are limited to initial research, whichhopefully will lead to expanded and more expensive research on largeranimals and/or humans. Accordingly, mice and rats may be well-suited forevaluating candidate nutrients such as lipoic acid, isoflavonoids, plantpolyphenols, omega-3 fatty acids, taurine, carnitine, etc., to evaluatetheir effects on ocular or vision defects, in tests that will not use orinclude any zeaxanthin or other carotenoids. Subsequently, after initialevaluations and rankings have been determined by means of initialtesting in mice or rats, the most promising candidates can then betested in more expensive tests that will involve zeaxanthin, usinganimals that metabolize carotenoids in a manner comparable to humans(such as Japanese quails or other suitable birds, or primates), or inhuman clinical trials.

It should also be recognized that mice, rats, and other rodents do nothave pigmented maculas; instead, in general, the only animals that useUV-absorbing carotenoids to protect their retinas are primates, and somespecies of birds. However, if rats are induced (by bile salts in theirdiets) to begin taking up substantial quantities of carotenoids intocirculating blood, at least some of those carotenoids will be depositedinto photoreceptors in the retina, and into the lens of the eye, therebyallowing at least some types of research on those structures.

3. Agents and Methods to Create and Emulate Disorders

Additional options that can be used to evaluate candidate ocular-activenutrients involves the use of certain drugs or diets, to induce certaintypes of damage that can emulate known ocular disorders. As one example,cataracts can be induced by a drug called buthionin sulfoximine (e.g.,Maitra et al 1996), or by feeding lab animals certain types ofhigh-starch diets (e.g., Borenshtein et al 2001). As another example,diabetes can be induced by drugs such as streptozotocin (e.g., Kowluruet al 2003) or allosan.

If the goal of a research project is to study a disorder that involvesabnormally high levels of cell growth (such as wet macular degeneration,with excessive blood vessel growth, or certain types of “proliferativeretinopathies”), pellets contain cell-stimulating hormones can beimplanted into an eye. Such research, using “vascular endothelial growthfactor” (VEGF) or “basic fibroblast growth factor” (bFGF), is describedin articles such as Yoon et al 2000 and Joussen et al 2000.

Various types of surgical or mechanical interventions can also be usedto emulate certain ocular disorders. As one example, clamping off anartery for a fixed period of time is used to create ischemia, then theclamp can be suddenly released, to create a “reperfusion” injuryinvolving oxygen free radicals. In addition, external methods can beused to accelerate certain types of visual impairment. Such methodsinclude, for example, increasing the intensity of ultraviolet and bluelight, and increasing the atmospheric oxygen concentrations, in the pensor rooms where lab animals are being kept.

Any of these methods can impose additional levels of ocular stress anlab animals, thereby substantially accelerating the rates at which theywill develop ocular disorders. Accordingly, various candidateocular-active nutrients can be evaluated for potency and efficacy, bymeasuring how effectivly they can delay, prevent, or reduce thedisorders that will arise from the stresses that were imposed on theanimals.

4. Japanese Quail and Other Birds

As mentioned above, some types of birds use carotenoid pigments to helpprotect their retinas against damage by UV light. In most bird species,these pigments are deposited throughout the entire retina, rather thanjust in a small central area comparable to the maculas of primates. Areview of the use of birds, in retinal research, is contained in Fite etal 1991. Japanese quail have become a widely used and accepted birdmodel for retinal testing, as described in articles such as Fite et al1993, Fite 1994. Detailed methods for testing this species, to evaluatethe ability of zeaxanthin or lutein to protect against retinal damagecaused by high-intensity lights, were described in Thomson et al 2002.

In addition, an albino strain of Japanese quail has been developed,which suffers from rapid lens degeneration and cataract formation.

5. Testing of Dogs and Livestock

Among the types of lab animals larger than rodents that are used invision testing, dogs and livestock tend to be used most commonly, forvarious reasons.

With respect to dogs, their irises (which are circular) are more similarto human and primate irises, than the vertical-slit irises of cats; inaddition, dogs also suffer fairly commonly from cataracts. They can alsobe induced to incur various types of retinopathies, and there arecertain aspects of their vision processing that are of interest toneurology researchers (including limitations in the ability of dogs togenerate nerve impulses that will help them recognize and identifythings, unless some type of motion is involved that will trigger a setof nerve cell firings). For all of these reasons, dogs are used fairlycommonly for ocular and vision research. While they are more expensivethan mice or rats, they are less expensive than primate studies or humanclinical trials. Accordingly, if dogs are being considered as apotential animal model for studies as disclosed herein, a network ofexperts who are already familiar with that type of research in dogs canbe located, quickly and easily, by a database search for publishedarticles describing vision research in dogs.

Research on eye components or other tissues from various livestockspecies (including pigs, cows, and sheep) is enabled by an importantfactor: these animals are killed, in large numbers, at known locationsand under controlled conditions (i.e., at slaughterhouses). Therefore,specialized treatment procedures can be carried out on livestock animalsshortly before they are killed, and the affected tissues can beharvested at a controlled time, soon thereafter. Alternately, othertypes of specialized procedures can be carried out on tissue that washarvested immediately after an animal is killed; these types of tissuesamples are usually perfused (i.e., placed in specialized equipment thatwill pump fluids with oxygen and nutrients through or around thetissue), to sustain the tissue in a condition where its cells remainviable and metabolically active for a span of hours or days after theanimal was killed. Compared to ocular tissue samples from mice or rats,ocular tissues from animals such as cows or pigs are much easier tohandle and work with, and they also provide more relevant results, ifdimensional factors are important (such as, for example, when thepermeation of a drug or nutrient into or through lens tissue isimportant).

6. Primate Tests

Primates include lemurs, monkeys, and apes. While they are expensive toraise, keep, and test, they nevertheless provide animal models that, insome situations, will provide better and more applicable and relevantdata than any other type of animal test, short of a human clinicaltrial. Therefore, they must be kept in mind as one option. In manysituations, to keep costs under control, it may be possible to“piggyback” a vision-related test on top of some other type of ongoingtest (such as a cancer-related test), using the same animals that arebeing tested for other purposes.

Human Clinical Trials and Meta-Trials

Based on the results of animal tests, as described above and asotherwise known to those skilled in the art, candidate formulations thathave performed well in such animal tests can be further evaluated, inclinical trials. As used herein and in common practice, the term“clinical” implies that the subjects will be humans, rather thanlaboratory animals.

Proper and lawful general procedures for carrying out human clinicaltrials are described in numerous published articles and books, and areknown to thousands of researchers, consultants, and other experts. Thosegeneral procedures and requirements will not be discussed or analyzedherein.

However, two aspects of such testing on humans deserve special note andconsideration herein.

The first special point worth noting is this: at least some types ofocular or vision-related tests can be designed to speed up the gatheringof useful data, when testing patients who are suffering from diseasesthat gradually manifest or grow worse over a long span of time, such asmultiple years. This type of accelerated data gathering can be enabledby various approaches, such as by focusing on selected patients who, atthe point in time when they will be tested, are entering or progressingthrough certain stages that involve accelerated and rapid degenerationand loss of vision acuity.

As one example, among most patients who suffer from the dry form ofmacular degeneration (which includes roughly 90% of all cases of maculardegeneration), their retinas will pass, at some point during thedisease, through an intermediate stage called “geographic atrophy”.During this stage, distinct patches and areas of degeneration in oraround the macula become visible (as indicated by certain types ofcellular debris, such as abnormally large pieces of drusen andlipofuscin), in certain types of photographs that can be taken of theretina.

When retinas suffering from dry macular degeneration reach this stage,and begin to suffer from “geographic atrophy” showing clear and distinctpatches of degeneration, they have begun (or will soon begin) to sufferfrom accelerated and rapid retinal degeneration. Briefly, this processcan be depicted, in a schematic manner, by using the “S-curve” shown inFIG. 5B. A person suffering from the dry form of macular degenerationtypically will spend several years, passing through slow, gradual, andincremental losses of visual acuity, sometimes without even noticingthat his or her vision is slowly growing worse (or sometimes choosing toremain silent about it, when they do notice it, for fear of beingordered to stop driving). This long slow stage is represented by theflat slope of the plateau to the left side of the sharper slope.

At some point in time, most victims of macular degeneration will reach astage when the gradually accumulating stresses seem to begin piling ontop of each other, and the person begins to lose visual acuity at anaccelerated rate that can no longer be ignored or hidden. When thisoccurs, if the patient visits an ophthalmologist and has his or her eyeschecked, he or she usually will be found to be in the stage called“geographic atrophy.” If effective steps are not taken to halt thespread of the damage, it usually will begin accelerating even faster,and will lead to a rapid and severe loss of visual acuity.

When it comes to clinical testing of candidate ocular-active nutrients,patients who are approaching or who have already entered a “rapidacceleration” stage of degeneration can be highly useful and helpful,for carrying out tests that are specially designed to provide relativelyrapid data, to help reveal which particular nutrients (out of thevarious candidates that are being tested) can be the most effective inpreventing further degeneration, when combined with zeaxanthin inorally-ingestible formulations and foodstuffs. Accordingly, anyone whois contemplating or designing tests on various candidate ocular-activenutrients, should be alert to the possibility of placing patients whoare at the “geographic atrophy” stage of macular degeneration (or at acomparable stage of any other ocular disorder) into a special testing orcontrol population, which can then be analyzed carefully over a shorterperiod of time than would otherwise be required.

Another important approach that should be carefully considered, byanyone who is contemplating or designing tests on candidateocular-active nutrients, involves tests that are usually referred to as“meta-trials”. In general, these types of tests involve numerousdiscrete and relatively small data-gathering centers, which are groupedor tied together in ways that allow the data from all of the multiplesmall centers to be compiled into a larger pool of consistent shareddata.

As an example, one of the most promising approaches to human testing ofvarious candidate ocular-active formulations as disclosed herein can usea network of cooperating optometrists and/or ophthalmologists, who arealready skilled in examining eyes. Any optometrist or ophthalmologistwho wishes to become involved in a meta-trial will need to be instructed(with video, written, or in-person instruction or training, asnecessary) in the exact procedures that will need to be followed by allpatients enrolled in a test, and by any clerical or healthcare workerswho will monitor and review the data gathered at that site.

The procedures that will be used can involve either double-blindedtrials, or open-label trials, depending on the desires and goals of thepeople, companies, or agencies who are organizing and running the study.Monitoring of results can involve any appropriate data-gatheringmethods, such as visual acuity tests by optometrists (which usuallymeasure “lines of resolution” on standardized eye charts), or morecomplicated tests by ophthalmologists (such as measurements of pigmentdensities in lenses or maculas).

Each participating optometrist or ophthalmologist will be responsiblefor gathering data at his or her site, and one or more workers at thecoordinatng office will be responsible for (i) creating reporting formsthat will help ensure that the data from different sites are uniform andconsistent, and (ii) monitoring the quality of the data coming fromnumerous sites. Participating optometrists or ophthalmologists will besupplied with consistent and exact formulations by a single coordinatingoffice, and if a trial is double-blinded, these products can be in theform of number-coded bottles, containing capsules or tablets that do notindicate whether the contents are test compounds, or controls.Presumably, any such controls likely will contain an anti-oxidantformulation that already has been shown to work at some level ofefficacy, such as the AREDS-1 formulation, which contains fairly highdosages of vitamins C and E, beta-carotene, and zinc.

If fifty optometrists or ophthalmologists (each continuing to work outof his or her normal office) are involved, and if each participatingoptometrist or ophthalmologist enrolls twenty patients in a controlgroup, and twenty patients in a test group, that will generate combinedtotals of 1000 patients in the control group, and 1000 patients in thetest group.

This approach can be used to generate relatively rapid yet statisticallypowerful data, without placing a huge burden on any one particularperson or location. Accordingly, meta-trials deserve careful attention,since they offer highly promising and relatively rapid yet relativelyinexpensive methods for carrying out human clinical trials, involvinglarge numbers of test and control subjects, on candidate ocular-activecombinations as described herein.

Candidate Ocular Active Nutrients

As mentioned in the Summary of the Invention, eight categories ofocular-active nutrients are identified herein, which are believed tooffer good and promising candidates for early evaluation, to determinewhether they can provide synergistic benefits when orally ingested alongwith zeaxanthin. These eight categories are summarized and describedbelow.

Most of the compounds mentioned below have one or more “chiral” carbonatoms, and therefore have different stereoisomers. As a general rule, ifany one particular stereoisomer is predominant, in plant sources or inanimals, then a strong presumption arises that steps should be taken toprovide the natural stereoisomer in a purified or semi-purified form, inany ocular-active nutrient that is being sold or administered to peoplewho wish to protect their eye health. Various known factors suggest thatthe eye is one of the most “stereo-specific” organs anywhere in thebody, and is highly sensitive to differences in stereoisomers. In manycases, this goal can be accomplished by using plant extracts, or byusing compounds that have been synthesized by chemically modifyingplant-derived stereospecific precursors.

1. Lipoic Acid

This is a fatty acid having 8 carbon atoms in a straight chain, with thecarboxy group at the #8 carbon atom, and with the #1 and #3 carbon atomsboth coupled to mercaptan groups (—SH, also called sulfhydryl or sulfidegroups). In the reduced form, the two mercaptan groups stay separatedfrom each other, with hydrogen protons attached to the sulfur atoms inboth pendant groups. In the oxidized form, the hydrogen protons areremoved, and the two sulfur atoms bond to each other, to form afive-member ring with the #1, #2, and #3 carbon atoms forming theremainder of the ring.

Because it can convert back and forth between a reduced form and anoxidized form, lipoic acid can help reduce and prevent unwantedoxidation of cells and tissues, and under some circumstances, it canalso help regenerate vitamin E (Stoyanovsky et al 1995). Other articlesthat describe lipoic acid's ability to protect ocular tissues in varioustests include Packer 1994, Obrosova et al 1998, Borenshtein et al 2001,Chidlow 2002, and Goralska et al 2003.

Maitra et al 1996 reported that the naturally-occurring “R”(dextrorotatory) stereoisomer has better anti-oxidant activity than theS (levorotatory) isomers that are found in synthetic racemic mixtures.Accordingly, lipoic acid preparations having pure or enriched Rstereoisomers are preferred for testing and evaluation as disclosedherein.

2. Omega-3 Fatty Acids

Certain types of compounds that animals must eat in their diets arecalled “essential fatty acids”, because (i) animals need them, mainlyfor cell membrane formation, but animals cannot synthesize them; (ii)they contain a chain of carbon atoms with a length (usually ranging fromabout 10 to about 24 carbon atoms) that will form a fatty substance thatis solid or semi-solid at room temperature; and (iii) the last carbonatom in the carbon chain is part of a carboxylic acid group (—COOH).

In humans, the three most important essential fatty acids aredocosa-hexaenoic acid (abbreviated as DHA), eicosa-pentaenoic acid(EPA), and alpha-linolenic acid (ALA). All three of these compound arecalled omega-3 fatty acids, since the #3 carbon atom (counting from thenon-acid end of the chain) is the first carbon atom that is involved inan unsaturated bond. All three of those omega-3 fatty acids are presentin relatively high concentrations in certain types of fish oils, andthey can also be obtained from other natural sources, such as certaintypes of marine algae. They are associated with a number of healthbenefits, including cardiovascular benefits, anti-cancer activity, etc.,so they are of substantial interest throughout the entire field ofdietary supplements, as described in articles such as Connor 2000.

Omega-6 fatty acids (with the first double-bond positioned between the#6 and #7 carbon atoms in the carbon chain) are more abundant in nature;however, their health benefits are not as great as for omega-3 fattyacids, and most people already get too many omega-6 fatty acids and notenough omega-3 fatty acids in their diets. Therefore, if a dietarysupplement contains a mixture of omega-3 and omega-6 fatty acids, itpreferably should contain at least about 30%, and preferably 50% ormore, of the omega-3 compounds.

Among the omega-3 fatty acids, DHA has a more important role inmammalian metabolism than EPA, and ALA is generally regarded as merely aprecursor to DHA and EPA. Therefore, in purified or semi-purifiedpreparations, DHA is generally the preferred compound, and it hasreceived the most study. Its activities and effects in eyes aredescribed in articles such as Jeffrey et al 2001, Polit et al 2001,Murayama et al 2002, and Rotstein et al 2003.

3. Plant-Derived Active Agents (Flavonoids, Anthocyanins, PlantPolyphenolics, and Phytonutrients)

A third category of candidate ocular-active nutrients that is ofinterest herein includes a number of plant-derived compounds, which canbe referred to by terms that include flavonoids (or bioflavonoids),anthocyanins, plant polyphenolics, or phytonutrients. These labelsoverlap heavily with each other, and compounds that fall within labelsare described in various articles such as Beecher 1999 and Beecher 2003.The molecular structures for each of the named compounds listed beloware publicly known, and can be located in various public sources (e.g.,the chemical structures of numerous flavonoids, both common and rare,are nicely illustrated and organized athttp://www.friedli.com/herbs/phytochem/flavonoids.html).

Compounds that fall within the categories of flavonoids, anthocyanins,plant polyphenolics, or phytonutrients can include either or both of thefollowing: (i) non-purified or semi-purified multi-component mixturesthat have been extracted from the fruits, leaves, seeds, nuts, or otherparts of various known plants, such as bilberry, grapeseed, green tea,or soybeans; or, (ii) specific known and purified compounds (or limitedmixtures of a small number of similar and related compounds) from suchplants, such as quercetin, genestein, diazedem, fisetin, luteolin,resveretrol, and pycogenol.

These and various other similar known agents have different specificactivites and roles, and each one needs to be considered separately. Forexample, most flavonoid compounds reduce the activity of an enzymecalled aldose reductase. This enzyme converts certain types ofbeneficial sugars (such as glucose) into sugar-alcohols (such assorbitol) that will cause problems if they accumulate in excessivequantities. Sorbitol is an important causative factor in cataractformation, especially among diabetics. Therefore, flavonoids thatinhibit aldose reductase enzymes can help prevent or slow down cataractformation (e.g., Jung et al 2002, Matsuda et al 2002).

The specific activities, in animal eyes, of any known plant polyphenol(or flavonoid, anthocyanin, phytonutrient, etc.) that has been studiedin animals can be identified fairly easily, by searching the freedatabase that is maintained by the National Library of Medicine. Asexamples, resveretrol reportedly can suppress vascularization (e.g.,Brakenhielm et al 2001), and is a good antioxidant and free radicalscavenger (Lorenz et al 2003), while genistein reportedly inhibitscertain protein kinase enzymes, and can help suppress unwanted types ofcell-signalling pathways (e.g., Yoon 2000).

4. Taurine

Taurine is the common name for 2-amino-ethane-sulfonic acid, a“conditionally essential nutrient” that is present in milk andelswehere. Taurine's ability to protect v ocular tissues in varioustypes of tests (especially involving diabetic pathologies) is describedin articles such as Devamanoharan et al 1998, Obrosova et al 1999 and2001, Chen et al 2000, Militante et al 2002, Pasantes-Morales et al2002, and DiLeo et al 2003.

5. Carnitine

L-Carnitine is a sulfur-containing amino acid (not one of the 20 primaryamino acids used in protein synthesis) that is formed in the liver andcertain other tissues. It is believed to facilitate the transport offatty acids into mitochondria, for certain types of oxidation. Certainesters of carnitine (mainly acetyl-L-carnitine) are preferred for oralingestion.

Carnitine's ability to help prevent or treat ocular disorders isdescribed in articles such as Pessotto et al 1997, Peluso et al 2001,Alagoz et al 2002, and Feher et al 2003. The acetyl-L-carnitineprecursor is one of three ingredients (along with omega-3 fatty acids,and coenzyme Q10) in an ocular formulation called PHOTOTROPTM, sold bythe Sigma Tau Company.

6. Coenzyme-Q10

An enzyme cofactor known as Coenzyme-Q10 (the Q stands for quinone) is aknown anti-oxidant that provides energy-related support to mitochondria.Mitochondria are organelles, inside animal cells, that are enclosedwithin their own membranes and that have their own set of genes (thesegenes even use their own special genetic code, which is slightlydifferent from the standard genetic code used in the nucleus of a cell).In a truly remarkable feat of adaptive biology, mitochondria actuallyare the descendants of tiny anaerobic bacteria, which invaded largercells billions of years ago, and which then established a symbioticrelationship with their host cells. In this symbiotic relationship, theinvaders-turned-guests carry out processes known as “oxidativephosphorylation”, which is a crucial part of energy metabolism in thehost cells. Because of this role, mitochondria are sometimes referred toas the “furnaces” that handle the burning operations that supply heatand power to the rest of the cell.

When mitochondria are under severe stress, they begin releasing certaintypes of cytochrome compounds, which will then begin acting assignalling compounds, which will activate a process called “apoptosis”,also referred to as “programmed cell death”. Apoptosis is a naturalprocess that is beneficial in most situations, since it gives tissuesand organs a way to clean up and get rid of dead and dying cells, andreplace them with newly-formed and healthy cells. However, in somesituations (especially involving neurons, which are extremely difficultand often impossible to replace), apoptosis can lead to severe problems,including (in eye tissues) the unprogrammed and unwanted death anddestruction of neurons in the retina. Therefore, by helping stabilizemitochondria, Coenzyme-Q10 can help prevent the release of mitochondrialcytochromes that would lead to unwanted cell deaths, in ocular tissuesthat are struggling to cope with a serious disorder.

As mentioned above, Coenzyme Q10 is one of the three ingredients in anocular formulation called PHOTOTROPTM, sold by the Sigma Tau Company.

7. Carnosine

Carnosine is a di-peptide, formed when alanine and histidine bond toeach other. It can bond to and quench aldehydes, which are potentiallydangerous reactive molecules that can otherwise cause random andunwanted modifications (such as glycosylation or crosslinking) toproteins. The most commonly used orally-ingestible form of carnosine isan ester precursor, N-alpha-acetyl-carnosine. Eyedrops containingcarnosine also have been developed and are being publicly sold inEurope.

The protective activities and effects of carnosine in ocular tissues aredescribed in articles such as Maichuk et al 1997, Hipkiss et al 1998,and Babizhayev et al 2002.

8. Glutathione Boosters

Glutathione is a tri-peptide molecule, formed by three amino acidslinked together, with cysteine in the middle. Cysteine has a highlyreactive sulfur group (—SH) as its side chain. This allows theglutathione tri-peptide to become bonded to other compounds.

With the help of enzymes such as glutathione-S-transferase, glutathionemost commonly gets bonded to waste metabolites. This makes the wasteproducts more soluble in water, which in turn helps cells and tissueseliminate those wastes, through pathways that typically end up in urine.

Since the glutathione system provides a useful pathway that helps cellsand tissues get rid of waste products, nutrients that can stimulate theproduction or metabolism of glutathione can help badly-stressed cellsand tissues cope more successfully with their waste-handling problems.One such nutrient is N-acetyl cysteine, an ester that when ingestedorally will release cysteine, the sulfur-containing amino acid that sitsat the center of the glutathione tri-peptide. Other candidates agentsthat are believed to boost glutathione production or metabolism includeselenium, pyridoxine, and riboflavin. These are disclosed, as agentsthat can help treat macular degeneration, in U.S. Pat. No. 5,075,116(LaHaye 1991).

The AREDS-1 Components

In addition to the eight categories of ocular-active nutrients listedabove (none of which were tested during the AREDS-1 trial in the1990's), three additional types of compounds that were tested in theAREDS-1 trial also deserve attention. These compounds are also discussedin U.S. Pat. No. 6,660,297 (Bartels et al 2003).

Tocopherol compounds, such as alpha-tocopherol (vitamin E), meritspecial attention, because of an important physiological factor.Carotenoids tend to be most effective, as antioxidants, in the presenceof relatively low oxygen concentrations. By contrast, tocopherols tendto become more and more effective, as antioxidants, when oxygenconcentrations grow higher. Therefore, a combination of zeaxanthin withone or more tocopherols is likely to provide a good “broad-spectrum”antioxidant, where each compound can work most effectively under theconditions where the other compound is weakest.

Vitamin C has its own well-known benefits, and it is one of the fewvitamins or anti-oxidants that is water-soluble. Therefore, if awater-soluble anti-oxidant such as Vitamin C is coadministered withzeaxanthin (a hydrophobic, oil-soluble anti-oxidant), the two of themtogether are likely to be more effective than either one can be byitself.

Zinc also has a crucially important and valuable role in biology,because it is the only essential mineral (or transition metal) that hasno reduction-oxidation potential. Its electroic charge is completelyneutral; it will not seek to take protons or electrons away fromproteins or DNA, and it will not seek to get rid of protons or electronsby pushing them off onto proteins or DNA. In addition, it can bond in astable manner to one, two, three, or even four other molecules.Therefore, it evolved into an essential cofactor in hundreds of enzymesand thousands of DNA-regulatory proteins, and it is very widely used byproteins to stabilize a variety of three-dimensional conformations,ranging from the protruding “finger domains” in zinc-finger proteins, tothe “deep cleft” domains in carbonic anhydrase enzymes. It also helpsstabilize cell membranes, promotes wound-healing, and even hassignificant microbicidal and bacteriostatic activity.

Because it is a known beneficial, stabilizing, membrane-protectingagent, oral dosages of zinc were tested, years ago, to determine whetherthey could help poeple suffering from macular degeneration and otherocular problems. The results were good, although not especially strong,as described in articles such as Newsome et al 1988, Yuzbasiyan et al1989, Hawkins 1991, Trempe 1992, and Beaumont 1993. Therefore, it wasincluded in the AREDS-1 trial, and the benefits it provided were: (i)strong enough to roughly match the benefits provided by a combination ofvitamins A, C, and E, and (ii) strong enough to push the benefitsoffered by vitamins A, C, and E into a higher category of significance.

Accordingly, zinc is regarded as one of the more promising candidateagents, for testing as described herein. However, it is suspected thatthe benefits of zinc, for at least most patients, likely can becompletely achieved by dosages in the range of about 40 mg/day (which isonly about half of the dosages used in the AREDS-1 trial), or possiblyeven less. Accordingly, if substantial synergistic benefits can beprovided by 40 mg/day or lower dosages of zinc, when combined withzeaxanthin, those lower dosages of zinc can help avoid various concernsover zinc-induced anemia, and/or the need for yet another additive (suchas copper sulfate), that were raised by the 80 mg dosages used in theAREDS-1 trial.

Thus, there has been shown and described a new and useful means foridentifying agents that can perform synergistically with zeaxanthin, inpharmaceutical, dietary, or food preparations that can help protect eyehealth and treat ocular disorders. Although this invention has beenexemplified for purposes of illustration and description by reference tocertain specific embodiments, it will be apparent to those skilled inthe art that various modifications, alterations, and equivalents of theillustrated examples are possible. Any such changes which derivedirectly from the teachings herein, and which do not depart from thespirit and scope of the invention, are deemed to be covered by thisinvention.

References

-   Alagoz G, et al, “L-carnitine in experimental retinal    ischemia-reperfusion injury,” Ophthalmologica. 2002 March-April;    216(2): 144-50-   Areias F M, et al, “Antioxidant effect of flavonoids after    ascorbate/Fe(2+)-induced oxidative stress in cultured retinal    cells,” Biochem Pharmacol. 2001 Jul. 1; 62(1): 111-8-   Babizhayev M A, et al, “Efficacy of N-acetylcarnosine in the    treatment of cataracts,” Drugs R D. 2002; 3(2): 87-103-   Beaumont P., “Zinc and macular degeneration,” Arch Ophthalmol. 111:    1023 (1993)-   Beecher G R, “Overview of dietary flavonoids: nomenclature,    occurrence and intake,” J Nutr. 2003 October; 133(10): 3248S-3254S-   Beecher G R, “Phytonutrients' role in metabolism: effects on    resistance to degenerative processes,” Nutr Rev. 1999 September;    57(9 Pt 2): S3-6-   Borenshtein D, et al, “Cataract development in diabetic sand rats    treated with alpha-lipoic acid and its gamma-linolenic acid    conjugate,” Diabetes Metab Res Rev. 2001 January-February; 17(1):    44-50-   Brakenhielm E, et al, “Suppression of angiogenesis, tumor growth,    and wound healing by resveratrol, a natural compound in red wine and    grapes,” FASEB J. 2001 August; 15(10): 1798-800-   Cao Y, et al, “Antiangiogenic mechanisms of diet-derived    polyphenols,” J Nutr Biochem. 2002 July; 13(7): 380-390-   Castillo M, et al, “Effects of hypoxia on retinal pigmented    epithelium cells: protection by antioxidants,” Ophthalmic Res. 2002    November-December; 34(6): 338-42-   Chen F, et al, “An experimental research of taurine on H2O2-induced    bovine lens epithelial cell apoptosis,” Zhonghua Yan Ke Za Zhi. 2000    July; 36(4): 272-4, 17-   Chidlow G, et al, “Alpha-lipoic acid protects the retina against    ischemia-reperfusion,” Neuropharmacology. 2002 November; 43(6):    1015-25-   Connor W E., “Importance of omega-3 fatty acids in health and    disease,” Am J Clin Nutr. 2000 January; 71(1 Suppl): 171S-5S.-   Devamanoharan P S, et al, “Oxidative stress to rat lens in vitro:    protection by taurine,” Free Radic Res. 1998 September; 29(3):    189-95-   DiLeo M A, et al, “Potential therapeutic effect of antioxidants in    experimental diabetic retina: a comparison between chronic taurine    and vitamin E plus selenium supplementations,” Free Radic Res. 2003    March; 37(3): 323-30-   Erlund I, et al, “Consumption of black currants, lingonberries and    bilberries increases serum quercetin concentrations,” Eur J Clin    Nutr. 2003 January; 57(1): 37-42-   Feher J, et al, “Mitotropic compounds for the treatment of    age-related macular degeneration. The metabolic approach and a pilot    study,” Ophthalmologica. 2003 September-October; 217(5): 351-7-   Goralska M, et al, “Alpha lipoic acid changes iron uptake and    storage in lens epithelial cells,” Exp Eye Res. 2003 February;    76(2): 241-8-   Hawkins W R., “Zinc supplementation for macular degeneration,” Arch    Ophthalmol. 109: 1345 (1991)-   Hipkiss A R, et al, “Pluripotent protective effects of carnosine, a    naturally occurring dipeptide,” Ann N Y Acad. Sci. 1998 Nov. 20;    854: 37-53-   Jeffrey B G, et al, “The role of docosahexaenoic acid in retinal    function,” Lipids. 2001 September; 36(9): 859-71-   Joussen A M, et al, “Treatment of corneal neovascularization with    dietary isoflavonoids and flavonoids,” Exp Eye Res. 2000 November;    71(5): 483-7-   Jung S H, et al, “Isoflavonoids from the rhizomes of Belamcanda    chinensis and their effects Qn aldose reductase and sorbitol    accumulation in streptozotocin induced diabetic rat tissues,” Arch    Pharm Res. 2002 June; 25(3): 306-12-   Kahkonen M P, et al, “Berry phenolics and their antioxidant    activity,” J Agric Food Chem. 2001 August; 49(8): 4076-82-   Kilic F, et al, “Modelling cortical cataractogenesis XX. In vitro    effect of alpha-lipoic acid on glutathione concentrations in lens in    model diabetic cataractogenesis,” Biochem Mol Biol Int. 1998    October; 46(3): 585-95-   Kocer I, et al, “Protection of the retina from ischemia-reperfusion    injury by L-carnitine in guinea pigs,” Eur J Ophthalmol. 2003    January-February; 13(1): 80-5-   Kowluru R A., “Diabetes-induced elevations in retinal oxidative    stress, protein kinase C and nitric oxide are interrelated,” Acta    Diabetol. 2001 December; 38(4): 179-85-   Kowluru R A, et al, “Diabetes-induced mitochondrial dysfunction in    the retina,” Invest Ophthalmol Vis Sci. 2003 December; 44(12):    5327-34-   Lorenz P, et al, “Oxyresveratrol and resveratrol are potent    antioxidants and free radical scavengers: effect on nitrosative and    oxidative stress derived from microglial cells,” Nitric Oxide. 2003    September; 9(2): 64-76-   Maichuk I F, et al, “[Development of carnosine eyedrops and    assessing their efficacy in corneal diseases] Vestn Oftalmol. 1997    November-December; 113(6): 27-31-   Maitra I, et al, “Stereospecific effects of R-lipoic acid on    buthionine sulfoximine-induced cataract formation in newborn rats,”    Biochem Biophys Res Commun. 1996 Apr. 16; 221(2): 422-9-   Manzanas L, et al, “Oral flavonoids, chromocarb diethylamine salt    and cyaminosides chloride, to eliminate lipoperoxidation    postvitrectomy,” Exp Eye Res. 2002 January; 74(1): 23-8-   Matsuda H, et al, “Structural requirements of flavonoids and related    compounds for aldose reductase inhibitory activity,” Chem Pharm Bull    (Tokyo). 2002 June; 50(6): 788-95-   Militante J D, et al, “Taurine: evidence of physiological function    in the retina,” Nutr Neurosci. 2002 April; 5(2): 75-90-   Murayama K, et al, “Fish oil (polyunsaturated fatty acid) prevents    ischemic-induced injury in the mammalian retina,” Exp Eye Res. 2002    June; 74(6): 671-6-   Newsome, D. A., et al, “Oral zinc in macular degeneration,” Arch.    Ophthalmol. 106: 192-198 (1988)-   Obrosova I G, et al, “Taurine counteracts oxidative stress and nerve    growth factor deficit in early experimental diabetic neuropathy,”    Exp Neurol. 2001 November; 172(1): 211-9-   Obrosova I, et al, “Diabetes-induced changes in lens antioxidant    status, glucose utilization and energy metabolism: effect of    DL-alpha-lipoic acid,” Diabetologia. 1998 December; 41(12): 1442-50-   Obrosova I G, et al, “Early changes in lipid peroxidation and    antioxidative defense in diabetic rat retina: effect of    DL-alpha-lipoic acid,” Eur J. Pharmacol. 2000 Jun. 9; 398(1): 139-46-   Obrosova I G, et al, “Effect of dietary taurine supplementation on    GSH and NAD(P)-redox status, lipid peroxidation, and energy    metabolism in diabetic precataractous lens,” Invest Ophthalmol Vis    Sci. 1999 March; 40(3): 680-8-   Okuyama H, et al, “alpha-linolenate-deficiency-induced alterations    in brightness discrimination learning behavior and retinal function    in rats,” World Rev Nutr Diet. 2001; 88: 3540-   Packer L., “Antioxidant properties of lipoic acid and its    therapeutic effects in prevention of diabetes complications and    cataracts,” Ann N Y Acad. Sci. 1994 Nov. 17; 738: 257-64-   Pasantes-Morales H, et al, “Treatment with taurine, diltiazem, and    vitamin E retards the progressive visual field reduction in    retinitis pigmentosa: a 3-year follow-up study,” Metab Brain Dis.    2002 September; 17(3) 183-97.-   Peluso G, et al, “Carnitine protects the molecular chaperone    activity of lens alpha-crystallin and decreases the    post-translational protein modifications induced by oxidative    stress,” FASEB J. 2001 July; 15(9): 1604-6-   Pessotto P, et al, “In experimental diabetes the decrease in the eye    of lens carnitine levels is an early important and selective event,”    Exp Eye Res. 1997 February; 64(2): 195-201-   Polit L, et al, “Effects of docosahexaenoic acid on retinal    development: cellular and molecular aspects,” Lipids. 2001    September; 36(9): 927-35-   Robert A M, et al, “[Protection of cornea against proteolytic    damage. Experimental study of procyanidolic oligomers (PCO) on    bovine cornea] J Fr Ophtalmol. 2002 April; 25(4): 351-5-   Rotstein N P, et al, “Protective effect of docosahexaenoic acid on    oxidative stress-induced apoptosis of retina photoreceptors,” Invest    Ophthalmol Vis Sci. 2003 May; 44(5): 2252-9-   Sparrow J R, et al, “A2E-epoxides damage DNA in retinal pigment    epithelial cells. Vitamin E and other antioxidants inhibit    A2E-epoxide formation,” J Biol. Chem. 2003 May 16; 278(20):    18207-13. Epub 2003 Mar. 19-   Stoyanovsky D A, et al, “Endogenous ascorbate regenerates vitamin E    in the retina directly and in combination with exogenous    dihydrolipoic acid,” Curr Eye Res. 1995 March; 14(3): 181-9-   Thomson L R, et al, “Elevated retinal zeaxanthin and prevention of    light-induced photoreceptor cell death in quail,” Invest Ophthalmol    Vis Sci. 2002 November; 43(11): 3538-49.-   Trempe C. L., “Zinc and macular degeneration,” Arch Ophtlalmol. 110:    1517 (1992)-   Yamakoshi J, et al, “Procyanidin-rich extract from grape seeds    prevents cataract formation in hereditary cataractous (ICR/f) rats,”    J Agric Food Chem. 2002 Aug. 14; 50(17): 4983-8-   Yoon H S, et al, “Genistein produces reduction in growth and induces    apoptosis of rat RPE-J cells,” Curr Eye Res. 2000 March; 20(3):    215-24-   Yuzbasiyan, G. V., et al, “The therapeutic use of zinc in macular    degeneration,” Arch Ophthalmol. 107: 1723-24 (1989)

1. A nutrient formulation for preventing or treating at least one oculardisorder in higher mammals, wherein said nutrient formulation comprises:a. a 3R-3′R stereoisomer of zeaxanthin, in a daily dosage of at least0.5 milligrams; and, b. at least two additional ocular-active nutrientsthat have been shown to have synergistic activity against at least onemammalian ocular disorder when combined with zeaxanthin, wherein saidsynergistic activity provided by said additional ocular-active nutrientsprovides greater efficacy, in preventing or treating at least one oculardisorder in humans, than can be achieved by zeaxanthin alone or by saidtwo ocular-active nutrients alone.
 2. The nutrient formulation of claim1, wherein at least one of said additional ocular-active nutrients ispresent in a stereoisomerically-enriched form, containing a dominantstereoisomer that is present in normal human diets.
 3. The nutrientformulation of claim 1, wherein at least one of said additionalocular-active nutrients is present in a form that provides sustainedrelease over a span of at least 3 hours following ingestion.
 4. Thenutrient formulation of claim 1, wherein said formulation also comprisesat least one agent that has been added to increase digestive uptake oflipophilic compounds.